CoChat
Sign Up
Cited by 185Autophagy in Disease and TherapyAlzheimer's disease research and treatmentsUbiquitin and proteasome pathways

SQSTM1/p62: a potential target for neurodegenerative disease

Open access
Ma, Shifan, Attarwala, Insiya Y., Xie, Xiang-Qun·2019·ACS Chemical Neuroscience
DOI 10.1021/acschemneuro.8b00516PMC PMC6712989
Open this paper in CoChat — free account

Abstract

Neurodegenerative diseases, characterized by a progressive loss of brain function, affect the lives of millions of individuals worldwide. The complexity of the brain poses a challenge for scientists trying to map the biochemical and physiological pathways to identify areas of pathological errors. Brain samples of patients with neurodegenerative diseases have been shown to contain large amounts of misfolded and abnormally aggregated proteins, resulting in dysfunction in certain brain centers. Removal of these abnormal molecules is essential in maintaining protein homeostasis and overall neuronal health. Macroautophagy is a major route by which cells achieve this. Administration of certain autophagy-enhancing compounds has been shown to provide therapeutic effects for individuals with neurodegenerative conditions. SQSTM1/p62 is a scaffold protein closely involved in the macroautophagy process. p62 functions to anchor the ubiquitinated proteins to the autophagosome membrane, promoting degradation of unwanted molecules. Modulators targeting p62 to induce autophagy and promote its protective pathways for aggregate protein clearance have high potential in the treatment of these conditions. Additionally, causal relationships have been found between errors in regulation of SQSTM1/p62 and the development of a variety of neurodegenerative disorders, including Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, and frontotemporal lobar degeneration. Furthermore, SQSTM1/p62 also serves as a signaling hub for multiple pathways associated with neurodegeneration, providing a potential therapeutic target in the treatment of neurodegenerative diseases. However, rational design of a p62-oriented autophagy modulator that can balance the negative and positive functions of multiple domains in p62 requires further efforts in the exploration of the protein structure and pathological basis.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1021/acschemneuro.8b00516

Cites

18 of 18 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • SCARB2 has been identified in several PD risk genome-wide association studies.

    “SCARB2 has been identified in several PD risk genome-wide association studies (GWAS).100–103”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [102]

    The section “Regulation of p62 in Parkinson’s Disease (PD)” discusses genetic factors in PD, including parkin, PINK1 and LRRK2, but does not identify SCARB2 as a PD risk locus. Searches of our copy for SCARB2 and for PD genome-wide association studies found no passage addressing the claimed finding; page numbers were not available. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 184

  1. [1]Choonara YE, Pillay V, du Toit LC, Modi G, Naidoo D, Ndesendo VM, and Sibambo SR (2009) Trends in the molecular pathogenesis and clinical therapeutics of common neurodegenerative disorders. Int. J. Mol. Sci. 10, 2510– 2557. 19582217 PMC2705504
  2. [2]Vadlamudi RK, and Shin J (1998) Genomic structure and promoter analysis of the p62 gene encoding a non-proteasomal multiubiquitin chain binding protein. FEBS Lett. 435, 138– 142. 9762895
  3. [5]Puissant A, Fenouille N, and Auberger P (2012) When autophagy meets cancer through p62/SQSTM1. American journal of cancer research 2, 397– 413. 22860231 PMC3410580
  4. [6]Nezis IP, and Stenmark H (2012) p62 at the interface of autophagy, oxidative stress signaling, and cancer. Antioxid. Redox Signaling 17, 786– 793. 22074114
  5. [7]Moscat J, Diaz-Meco MT, and Wooten MW (2007) Signal integration and diversification through the p62 scaffold protein. Trends Biochem. Sci. 32, 95– 100. 17174552
  6. [8]Manley S, Williams JA, and Ding W-X (2013) Role of p62/SQSTM1 in liver physiology and pathogenesis. Exp. Biol. Med. 238, 525– 538. PMC4096157 23856904
  7. [9]Pickford F, Masliah E, Britschgi M, Lucin K, Narasimhan R, Jaeger PA, Small S, Spencer B, Rockenstein E, Levine B, and Wyss-Coray T (2008) The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid β accumulation in mice. J. Clin. Invest. 118, 2190– 2199. 18497889 PMC2391284
  8. [10]Bjørkøy G, Lamark T, Brech A, Outzen H, Perander M, Øvervatn A, Stenmark H, and Johansen T (2005) p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J. Cell Biol. 171, 603– 614. 16286508 PMC2171557
  9. [11]Mathew R, Karp CM, Beaudoin B, Vuong N, Chen G, Chen H-Y, Bray K, Reddy A, Bhanot G, Gelinas C, (2009) Autophagy suppresses tumorigenesis through elimination of p62. Cell 137, 1062– 1075. 19524509 PMC2802318
  10. [12]Moscat J, and Diaz-Meco MT (2012) p62: a versatile multitasker takes on cancer. Trends Biochem. Sci. 37, 230– 236. 22424619 PMC3531712
  11. [13]Ebrahimi-Fakhari D, Wahlster L, Hoffmann GF, and Kölker S (2014) Emerging role of autophagy in pediatric neurodegenerative and neurometabolic diseases. Pediatr. Res. 75, 217– 226. 24165736
  12. [15]Zheng Q, Li J, and Wang X (2009) Interplay between the ubiquitin-proteasome system and autophagy in proteinopathies. International journal of physiology, pathophysiology and pharmacology 1, 127. PMC2856956 20411034
  13. [16]Ihse E, Ybo A, Suhr O, Lindqvist P, Backman C, and Westermark P (2008) Amyloid fibril composition is related to the phenotype of hereditary transthyretin V30M amyloidosis. J. Pathol. 216, 253– 261. 18729067
  14. [18]Marcora MS, Fernandez-Gamba AC, Avendano LA, Rotondaro C, Podhajcer OL, Vidal R, Morelli L, Ceriani MF, and Castano EM (2014) Amyloid peptides ABri and ADan show differential neurotoxicity in transgenic Drosophila models of familial British and Danish dementia. Mol. Neurodegener. 9, 5. 24405716 PMC3898387
  15. [19]Haack TB, Ignatius E, Calvo-Garrido J, Iuso A, Isohanni P, Maffezzini C, Lönnqvist T, Suomalainen A, Gorza M, Kremer LS, Graf E, Hartig M, Berutti R, Paucar M, Svenningsson P, Stranneheim H, Brandberg G, Wedell A, Kurian MA, Hayflick SA, Venco P, Tiranti V, Strom TM, Dichgans M, Horvath R, Holinski-Feder E, Freyer C, Meitinger T, Prokisch H, Senderek J, Wredenberg A, Carroll CJ, and Klopstock T (2016) Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy. Am. J. Hum. Genet. 99, 735– 743. 27545679 PMC5010644
  16. [22]Vidal RL, Matus S, Bargsted L, and Hetz C (2014) Targeting autophagy in neurodegenerative diseases. Trends Pharmacol. Sci. 35, 583– 591. 25270767
  17. [23]Nixon RA (2013) The role of autophagy in neuro-degenerative disease. Nat. Med. 19, 983– 997. 23921753
  18. [24]Nascimento-Ferreira I, Santos-Ferreira T, Sousa-Ferreira L, Auregan G, Onofre I, Alves S, Dufour N, Colomer Gould VF, Koeppen A, Déglon N, and Pereira de Almeida L (2011) Overexpression of the autophagic beclin-1 protein clears mutant ataxin-3 and alleviates Machado–Joseph disease. Brain 134, 1400– 1415. 21478185
  19. [25]Wills J, Credle J, Oaks AW, Duka V, Lee J-H, Jones J, and Sidhu A (2012) Paraquat, but not maneb, induces synuclein-opathy and tauopathy in striata of mice through inhibition of proteasomal and autophagic pathways. PLoS One 7, No. e30745. PMC3264632 22292029
  20. [26]Shibata M, Lu T, Furuya T, Degterev A, Mizushima N, Yoshimori T, MacDonald M, Yankner B, and Yuan J (2006) Regulation of intracellular accumulation of mutant Huntingtin by Beclin 1. J. Biol. Chem. 281, 14474– 14485. 16522639
  21. [27]Wu J. c., Qi L, Wang Y, Kegel KB, Yoder J, Difiglia M, Qin Z. h., and Lin F (2012) The regulation of N-terminal Huntingtin (Htt552) accumulation by Beclin1. Acta Pharmacol. Sin. 33, 743– 751. 22543707 PMC4010368
  22. [28]Spencer B, Potkar R, Trejo M, Rockenstein E, Patrick C, Gindi R, Adame A, Wyss-Coray T, and Masliah E (2009) Beclin 1 gene transfer activates autophagy and ameliorates the neuro-degenerative pathology in α-synuclein models of Parkinson’s and Lewy body diseases. J. Neurosci. 29, 13578– 13588. 19864570 PMC2812014
  23. [29]Nassif M, Valenzuela V, Rojas-Rivera D, Vidal R, Matus S, Castillo K, Fuentealba Y, Kroemer G, Levine B, and Hetz C (2014) Pathogenic role of BECN1/Beclin 1 in the development of amyotrophic lateral sclerosis. Autophagy 10, 1256– 1271. 24905722 PMC4203551
  24. [30]Tokuda E, Brannstrom T, Andersen PM, and Marklund SL (2016) Low autophagy capacity implicated in motor system vulnerability to mutant superoxide dismutase. Acta Neuropathologica Communications 4, 6. 26810478 PMC4727314
  25. [31]Mealer RG, Murray AJ, Shahani N, Subramaniam S, and Snyder SH (2014) Rhes, a striatal-selective protein implicated in Huntington disease, binds beclin-1 and activates autophagy. J. Biol. Chem. 289, 3547– 3554. 24324270 PMC3916556
  26. [32]Lonskaya I, Hebron ML, Desforges NM, Franjie A, and Moussa CEH (2013) Tyrosine kinase inhibition increases functional parkin Beclin 1 interaction and enhances amyloid clearance and cognitive performance. EMBO molecular medicine 5, 1247– 1262. 23737459 PMC3944464
  27. [33]Arena G, Gelmetti V, Torosantucci L, Vignone D, Lamorte G, De Rosa P, Cilia E, Jonas E, and Valente EM (2013) PINK1 protects against cell death induced by mitochondrial depolarization, by phosphorylating Bcl-xL and impairing its pro-apoptotic cleavage. Cell Death Differ. 20, 920– 930. 23519076 PMC3679455
  28. [34]Zavodszky E, Seaman MN, Moreau K, Jimenez-Sanchez M, Breusegem SY, Harbour ME, and Rubinsztein DC (2014) Mutation in VPS35 associated with Parkinson’s disease impairs WASH complex association and inhibits autophagy. Nat. Commun. 5, 3828. 24819384 PMC4024763
  29. [35]Ramesh Babu J, Lamar Seibenhener M, Peng J, Strom AL, Kemppainen R, Cox N, Zhu H, Wooten MC, Diaz Meco MT, Moscat J, and Wooten MW (2008) Genetic inactivation of p62 leads to accumulation of hyperphosphorylated tau and neuro-degeneration. J. Neurochem. 106, 107– 120. 18346206
  30. [37]Komatsu M, Waguri S, Chiba T, Murata S, Iwata J. i., Tanida I, Ueno T, Koike M, Uchiyama Y, Kominami E, and Tanaka K (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880– 884. 16625205
  31. [38]Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K, Saito I, Okano H, and Mizushima N (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885– 889. 16625204
  32. [39]Metzger S, Saukko M, Van Che H, Tong L, Puder Y, Riess O, and Nguyen HP (2010) Age at onset in Huntington’s disease is modified by the autophagy pathway: implication of the V471A polymorphism in Atg7. Hum. Genet. 128, 453– 459. 20697744
  33. [40]Lee J-H, Yu WH, Kumar A, Lee S, Mohan PS, Peterhoff CM, Wolfe DM, Martinez-Vicente M, Massey AC, Sovak G, (2010) Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 141, 1146– 1158. 20541250 PMC3647462
  34. [41]Yang D-S, Stavrides P, Mohan PS, Kaushik S, Kumar A, Ohno M, Schmidt SD, Wesson D, Bandyopadhyay U, Jiang Y, (2011) Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer’s disease ameliorates amyloid pathologies and memory deficits. Brain 134, 258– 277. 21186265 PMC3009842
  35. [42]Dehay B, Ramirez A, Martinez-Vicente M, Perier C, Canron M-H, Doudnikoff E, Vital A, Vila M, Klein C, and Bezard E (2012) Loss of P-type ATPase ATP13A2/PARK9 function induces general lysosomal deficiency and leads to Parkinson disease neurodegeneration. Proc. Natl. Acad. Sci. U. S. A. 109, 9611– 9616. 22647602 PMC3386132
  36. [43]Dehay B, Bové J, Rodríguez-Muela N, Perier C, Recasens A, Boya P, and Vila M (2010) Pathogenic lysosomal depletion in Parkinson’s disease. J. Neurosci. 30, 12535– 12544. 20844148 PMC6633458
  37. [44]Caccamo A, Majumder S, Richardson A, Strong R, and Oddo S (2010) Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-β, and tau effects on cognitive impairments. J. Biol. Chem. 285, 13107– 13120. 20178983 PMC2857107
  38. [45]Majumder S, Richardson A, Strong R, and Oddo S (2011) Inducing autophagy by rapamycin before, but not after, the formation of plaques and tangles ameliorates cognitive deficits. PLoS One 6, No. e25416. PMC3182203 21980451
  39. [47]Pavel M, Imarisio S, Menzies FM, Jimenez-Sanchez M, Siddiqi FH, Wu X, Renna M, O’Kane CJ, Crowther DC, and Rubinsztein DC (2016) CCT complex restricts neuropathogenic protein aggregation via autophagy. Nat. Commun. 7, 13821. 27929117 PMC5155164
  40. [49]Malagelada C, Jin ZH, Jackson-Lewis V, Przedborski S, and Greene LA (2010) Rapamycin Protects against Neuron Death in In Vitro andIn Vivo Models of Parkinson’s Disease. J. Neurosci. 30, 1166– 1175. 20089925 PMC2880868
  41. [50]Wang IF, Guo B-S, Liu Y-C, Wu C-C, Yang C-H, Tsai K-J, and Shen C-KJ (2012) Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43. Proc. Natl. Acad. Sci. U. S. A. 109, 15024– 15029. 22932872 PMC3443184
  42. [51]Zhang X, Li L, Chen S, Yang D, Wang Y, Zhang X, Wang Z, and Le W (2011) Rapamycin treatment augments motor neuron degeneration in SOD1G93A mouse model of amyotrophic lateral sclerosis. Autophagy 7, 412– 425. 21193837
  43. [52]Liu WJ, Ye L, Huang WF, Guo LJ, Xu ZG, Wu HL, Yang C, and Liu HF (2016) p62 links the autophagy pathway and the ubiqutin–proteasome system upon ubiquitinated protein degradation. Cell. Mol Biol. Lett. 21, 29. 28536631 PMC5415757
  44. [53]van de Donk NWCJ, Moreau P, Plesner T, Palumbo A, Gay F, Laubach JP, Malavasi F, Avet-Loiseau H, Mateos M-V, and Sonneveld P (2016) Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma. Blood 127, 681. 26631114
  45. [54]Tanji K, Zhang HX, Mori F, Kakita A, Takahashi H, and Wakabayashi K (2012) p62/sequestosome 1 binds to TDP 43 in brains with frontotemporal lobar degeneration with TDP 43 inclusions. J. Neurosci. Res. 90, 2034– 2042. 22674379
  46. [55]Geetha T, Zheng C, McGregor WC, White BD, Diaz-Meco MT, Moscat J, and Babu JR (2012) TRAF6 and p62 inhibit amyloid β-induced neuronal death through p75 neurotrophin receptor. Neurochem. Int. 61, 1289– 1293. 23017601 PMC3972807
  47. [56]Seneci P (2014) Molecular Targets in Protein Misfolding and Neurodegenerative Disease, Academic Press.
  48. [57]Puissant A, Fenouille N, and Auberger P (2012) When autophagy meets cancer through p62/SQSTM1. Am. J. Cancer Res. 2, 397– 413. 22860231 PMC3410580
  49. [58]Bortnik S, and Gorski SM (2017) Clinical Applications of Autophagy Proteins in Cancer: From Potential Targets to Biomarkers. Int. J. Mol. Sci. 18, 1496. PMC5535986 28696368
  50. [59]He Y, Zhao X, Subahan NR, Fan L, Gao J, and Chen H (2014) The prognostic value of autophagy-related markers beclin-1 and microtubule-associated protein light chain 3B in cancers: a systematic review and meta-analysis. Tumor Biol. 35, 7317– 7326. 24838948
  51. [60]Zhang J, and Ney PA (2009) Role of BNIP3 and NIX in cell death, autophagy, and mitophagy. Cell Death Differ. 16, 939. 19229244 PMC2768230
  52. [61]Birgisdottir ÅB, Lamark T, and Johansen T (2013) The LIR motif – crucial for selective autophagy. Journal of Cell Science 126, 3237– 3247. 23908376
  53. [62]Seillier M, Peuget S, Gayet O, Gauthier C, N’Guessan P, Monte M, Carrier A, Iovanna JL, and Dusetti NJ (2012) TP53INP1, a tumor suppressor, interacts with LC3 and ATG8-family proteins through the LC3-interacting region (LIR) and promotes autophagy-dependent cell death. Cell Death Differ. 19, 1525. 22421968 PMC3422476
  54. [63]Wooten MW, Hu X, Babu JR, Seibenhener ML, Geetha T, Paine MG, and Wooten MC (2006) Signaling, polyubiquitination, trafficking, and inclusions: sequestosome 1/p62’s role in neurodegenerative disease. J. Biomed. Biotechnol. 2006, 62079. 17047309 PMC1559922
  55. [64]Seibenhener ML, Babu JR, Geetha T, Wong HC, Krishna NR, and Wooten MW (2004) Sequestosome 1/p62 is a polyubiquitin chain binding protein involved in ubiquitin proteasome degradation. Molecular and cellular biology 24, 8055– 8068. 15340068 PMC515032
  56. [65]Babu JR, Geetha T, and Wooten MW (2005) Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal degradation. J. Neurochem. 94, 192– 203. 15953362
  57. [66]Geetha T, Seibenhener ML, Chen L, Madura K, and Wooten MW (2008) p62 serves as a shuttling factor for TrkA interaction with the proteasome. Biochem. Biophys. Res. Commun. 374, 33– 37. 18598672 PMC2561188
  58. [67]Myeku N, and Figueiredo-Pereira ME (2011) Dynamics of the degradation of ubiquitinated proteins by proteasomes and autophagy: association with sequestosome 1/p62. J. Biol. Chem. 286, 22426– 22440. 21536669 PMC3121389
  59. [68]Korolchuk VI, Mansilla A, Menzies FM, and Rubinsztein DC (2009) Autophagy inhibition compromises degradation of ubiquitin-proteasome pathway substrates. Mol. Cell 33, 517– 527. 19250912 PMC2669153
  60. [69]P. McNaught KS St, Belizaire R, Isacson O, Jenner P, and Olanow CW. (2003) Altered proteasomal function in sporadic Parkinson’s disease. Exp. Neurol. 179, 38– 46. 12504866
  61. [70]McNaught KS, and Jenner P (2001) Proteasomal function is impaired in substantia nigra in Parkinson’s disease. Neurosci. Lett. 297, 191– 194. 11137760
  62. [71]Chen L, Thiruchelvam MJ, Madura K, and Richfield EK (2006) Proteasome dysfunction in aged human alpha-synuclein transgenic mice. Neurobiol. Dis. 23, 120– 126. 16713278
  63. [72]Snyder H, Mensah K, Theisler C, Lee J, Matouschek A, and Wolozin B (2003) Aggregated and monomeric alpha-synuclein bind to the S6’ proteasomal protein and inhibit proteasomal function. J. Biol. Chem. 278, 11753– 11759. 12551928
  64. [73]Tseng BP, Green KN, Chan JL, Blurton-Jones M, and LaFerla FM (2008) Abeta inhibits the proteasome and enhances amyloid and tau accumulation. Neurobiol. Aging 29, 1607– 1618. 17544172 PMC2664168
  65. [74]Lopez Salon M, Pasquini L, Besio Moreno M, Pasquini JM, and Soto E (2003) Relationship between beta-amyloid degradation and the 26S proteasome in neural cells. Exp. Neurol. 180, 131– 143. 12684027
  66. [75]Song S, Kim SY, Hong YM, Jo DG, Lee JY, Shim SM, Chung CW, Seo SJ, Yoo YJ, Koh JY, Lee MC, Yates AJ, Ichijo H, and Jung YK (2003) Essential role of E2–25K/Hip-2 in mediating amyloid-beta neurotoxicity. Mol. Cell 12, 553– 563. 14527403
  67. [76]Oh S, Hong HS, Hwang E, Sim HJ, Lee W, Shin SJ, and Mook-Jung I (2005) Amyloid peptide attenuates the proteasome activity in neuronal cells. Mech. Ageing Dev. 126, 1292– 1299. 16153690
  68. [77]Keller JN, Hanni KB, and Markesbery WR (2000) Impaired proteasome function in Alzheimer’s disease. J. Neurochem. 75, 436– 439. 10854289
  69. [78]Urushitani M, Kurisu J, Tsukita K, and Takahashi R (2002) Proteasomal inhibition by misfolded mutant superoxide dismutase 1 induces selective motor neuron death in familial amyotrophic lateral sclerosis. J. Neurochem. 83, 1030– 1042. 12437574
  70. [79]Seo H, Sonntag KC, and Isacson O (2004) Generalized brain and skin proteasome inhibition in Huntington’s disease. Ann. Neurol. 56, 319– 328. 15349858
  71. [80]Seo H, Sonntag KC, Kim W, Cattaneo E, and Isacson O (2007) Proteasome activator enhances survival of Huntington’s disease neuronal model cells. PLoS One 2, No. e238. PMC1800909 17327906
  72. [81]Kristiansen M, Deriziotis P, Dimcheff DE, Jackson GS, Ovaa H, Naumann H, Clarke AR, van Leeuwen FW, Menendez-Benito V, Dantuma NP, Portis JL, Collinge J, and Tabrizi SJ (2007) Disease-associated prion protein oligomers inhibit the 26S proteasome. Mol. Cell 26, 175– 188. 17466621
  73. [82]Lobanova ES, Finkelstein S, Skiba NP, and Arshavsky VY (2013) Proteasome overload is a common stress factor in multiple forms of inherited retinal degeneration. Proc. Natl. Acad. Sci. U. S. A. 110, 9986– 9991. 23716657 PMC3683722
  74. [84]Bett JS, Goellner GM, Woodman B, Pratt G, Rechsteiner M, and Bates GP (2006) Proteasome impairment does not contribute to pathogenesis in R6/2 Huntington’s disease mice: exclusion of proteasome activator REGgamma as a therapeutic target. Hum. Mol Genet. 15, 33– 44. 16311253
  75. [85]Ding Q, Lewis JJ, Strum KM, Dimayuga E, Bruce-Keller AJ, Dunn JC, and Keller JN (2002) Polyglutamine expansion, protein aggregation, proteasome activity, and neural survival. J. Biol. Chem. 277, 13935– 13942. 11782460
  76. [86]Czirr E, and Wyss-Coray T (2012) The immunology of neurodegeneration. J. Clin. Invest. 122, 1156– 1163. 22466657 PMC3315444
  77. [87]Dantuma NP, and Bott LC (2014) The ubiquitin-proteasome system in neurodegenerative diseases: precipitating factor, yet part of the solution. Front. Mol. Neurosci. 7, 70. 25132814 PMC4117186
  78. [88]Liu Y, Fallon L, Lashuel HA, Liu Z, and Lansbury PT Jr. (2002) The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson’s disease susceptibility. Cell 111, 209– 218. 12408865
  79. [89]Gong B, Cao Z, Zheng P, Vitolo OV, Liu S, Staniszewski A, Moolman D, Zhang H, Shelanski M, and Arancio O (2006) Ubiquitin hydrolase Uch-L1 rescues beta-amyloid-induced decreases in synaptic function and contextual memory. Cell 126, 775– 788. 16923396
  80. [90]Chung JY, Park HR, Lee SJ, Lee SH, Kim JS, Jung YS, Hwang SH, Ha NC, Seol WG, Lee J, and Park BJ (2013) Elevated TRAF2/6 expression in Parkinson’s disease is caused by the loss of Parkin E3 ligase activity. Lab. Invest. 93, 663– 676. 23608757
  81. [91]Rosen KM, Moussa CE, Lee HK, Kumar P, Kitada T, Qin G, Fu Q, and Querfurth HW (2010) Parkin reverses intracellular beta-amyloid accumulation and its negative effects on proteasome function. J. Neurosci. Res. 88, 167– 178. 19610108 PMC2844439
  82. [92]Hong X, Liu J, Zhu G, Zhuang Y, Suo H, Wang P, Huang D, Xu J, Huang Y, Yu M, Bian M, Sheng Z, Fei J, Song H, Behnisch T, and Huang F (2014) Parkin overexpression ameliorates hippocampal long-term potentiation and beta-amyloid load in an Alzheimer’s disease mouse model. Hum. Mol. Genet. 23, 1056– 1072. 24105468
  83. [93]Zheng Q, Huang T, Zhang L, Zhou Y, Luo H, Xu H, and Wang X (2016) Dysregulation of Ubiquitin-Proteasome System in Neurodegenerative Diseases. Front. Aging Neurosci. 8, 303. 28018215 PMC5156861
  84. [94]Sahara N, Murayama M, Mizoroki T, Urushitani M, Imai Y, Takahashi R, Murata S, Tanaka K, and Takashima A (2005) In vivo evidence of CHIP up-regulation attenuating tau aggregation. J. Neurochem. 94, 1254– 1263. 16111477
  85. [95]Kumar P, Ambasta RK, Veereshwarayya V, Rosen KM, Kosik KS, Band H, Mestril R, Patterson C, and Querfurth HW (2007) CHIP and HSPs interact with beta-APP in a proteasome-dependent manner and influence Abeta metabolism. Hum. Mol. Genet. 16, 848– 864. 17317785
  86. [96]Ko HS, Bailey R, Smith WW, Liu Z, Shin JH, Lee YI, Zhang YJ, Jiang H, Ross CA, Moore DJ, Patterson C, Petrucelli L, Dawson TM, and Dawson VL (2009) CHIP regulates leucine-rich repeat kinase-2 ubiquitination, degradation, and toxicity. Proc. Natl. Acad. Sci. U. S. A. 106, 2897– 2902. 19196961 PMC2650345
  87. [97]Kalia LV, Kalia SK, Chau H, Lozano AM, Hyman BT, and McLean PJ (2011) Ubiquitinylation of alpha-synuclein by carboxyl terminus Hsp70-interacting protein (CHIP) is regulated by Bcl-2-associated athanogene 5 (BAG5). PLoS One 6, No. e14695. PMC3040167 21358815
  88. [98]Imai Y, Soda M, Hatakeyama S, Akagi T, Hashikawa T, Nakayama KI, and Takahashi R (2002) CHIP is associated with Parkin, a gene responsible for familial Parkinson’s disease, and enhances its ubiquitin ligase activity. Mol. Cell 10, 55– 67. 12150907
  89. [99]Miller VM, Nelson RF, Gouvion CM, Williams A, Rodriguez-Lebron E, Harper SQ, Davidson BL, Rebagliati MR, and Paulson HL. (2005) CHIP suppresses polyglutamine aggregation and toxicity in vitro and in vivo. J. Neurosci. 25, 9152– 9161. 16207874 PMC6725774
  90. [100]Komatsu M, Kageyama S, and Ichimura Y (2012) p62/SQSTM1/A170: physiology and pathology. Pharmacol. Res. 66, 457– 462. 22841931
  91. [101]Moscat J, Diaz-Meco MT, Albert A, and Campuzano S (2006) Cell signaling and function organized by PB1 domain interactions. Mol. Cell 23, 631– 640. 16949360
  92. [102]Du Y, Wooten MC, and Wooten MW (2009) Oxidative damage to the promoter region of SQSTM1/p62 is common to neurodegenerative disease. Neurobiol Dis. 35, 302– 310. 19481605 PMC2718328
  93. [103]Kuusisto E (2004) Role of the p62 protein in the formation of neuropathological cytoplasmic inclusions, Doctoral Dissertation, University of Kuopio.
  94. [104]Salminen A, Kaarniranta K, Haapasalo A, Hiltunen M, Soininen H, and Alafuzoff I (2012) Emerging role of p62/sequestosome-1 in the pathogenesis of Alzheimer’s disease. Prog. Neurobiol. 96, 87– 95. 22138392
  95. [105]Sanz L, Diaz Meco MT, Nakano H, and Moscat J (2000) The atypical PKC interacting protein p62 channels NF κB activation by the IL 1–TRAF6 pathway. EMBO journal 19, 1576– 1586. 10747026 PMC310227
  96. [106]Swat MJ, Moodie S, Wimalaratne SM, Kristensen NR, Lavielle M, Mari A, Magni P, Smith MK, Bizzotto R, Pasotti L, Mezzalana E, Comets E, Sarr C, Terranova N, Blaudez E, Chan P, Chard J, Chatel K, Chenel M, Edwards D, Franklin C, Giorgino T, Glont M, Girard P, Grenon P, Harling K, Hooker AC, Kaye R, Keizer R, Kloft C, Kok JN, Kokash N, Laibe C, Laveille C, Lestini G, Mentre F, Munafo A, Nordgren R, Nyberg H,B, Parra-Guillen ZP, Plan E, Ribba B, Smith G, Troconiz IF, Yvon F, Milligan PA, Harnisch L, Karlsson M, Hermjakob H, and Le Novere N. (2015) Pharmacometrics Markup Language (PharmML): Opening New Perspectives for Model Exchange in Drug Development. CPT: Pharmacometrics Syst. Pharmacol. 4, 316– 319. 26225259 PMC4505825
  97. [107]Moscat J, and Diaz-Meco MT (2009) p62 at the crossroads of autophagy, apoptosis, and cancer. Cell 137, 1001– 1004. 19524504 PMC3971861
  98. [108]Kaltschmidt B, and Kaltschmidt C (2009) NF-κB in the Nervous System. Cold Spring Harbor Perspect. Biol. 1, a001271. PMC2773634 20066105
  99. [109]Nakamura K, Kimple AJ, Siderovski DP, and Johnson GL (2010) PB1 Domain Interaction of p62/Sequestosome 1 and MEKK3 Regulates NF-κB Activation. J. Biol. Chem. 285, 2077– 2089. 19903815 PMC2804364
  100. [110]Ramesh Babu J, Lamar Seibenhener M, Peng J, Strom A-L, Kemppainen R, Cox N, Zhu H, Wooten MC, Diaz-Meco MT, Moscat J, and Wooten MW (2008) Genetic inactivation ofp62 leads to accumulation of hyperphosphorylated tau and neuro-degeneration. J. Neurochem. 106, 107– 120. 18346206
  101. [111]Puri R, Suzuki T, Yamakawa K, and Ganesh S (2009) Hyperphosphorylation and Aggregation of Tau in Laforin-deficient Mice, an Animal Model for Lafora Disease. J. Biol. Chem. 284, 22657– 22663. 19542233 PMC2755673
  102. [113]Hadi TMA (2014) The role of p62 in osteoclastogenesis and paget’s disease of bone, Doctoral dissertation, Virginia Commonwealth University. Retrieved from: https://scholarscompass.vcu.edu/etd/3312.
  103. [114]Lee SJ, Pfluger PT, Kim JY, Nogueiras R, Duran A, Pagès G, Pouysségur J, Tschöp MH, Diaz-Meco MT, and Moscat J (2010) A functional role for the p62–ERK1 axis in the control of energy homeostasis and adipogenesis. EMBO Rep. 11, 226– 232. 20154642 PMC2838704
  104. [115]Diaz-Meco MT, and Moscat J (2012) The atypical PKCs in inflammation: NF-κB and beyond. Immunological reviews 246, 154– 167. 22435553 PMC3531713
  105. [116]Yan XY, Zhang Y, Zhang JJ, Zhang LC, Liu YN, Wu Y, Xue YN, Lu SY, Su J, and Sun LK (2017) p62/SQSTM1 as an oncotarget mediates cisplatin resistance through activating RIP1 NF κB pathway in human ovarian cancer cells. Cancer Science 108, 1405– 1413. 28498503 PMC5497928
  106. [117]Ofengeim D, and Yuan J (2013) Regulation of RIP1 kinase signaling at the crossrods of inflammation and cell death. Nat. Rev. Mol. Cell Biol. 14, 727. 24129419
  107. [118]Duran A, Amanchy R, Linares JF, Joshi J, Abu-Baker S, Porollo A, Hansen M, Moscat J, and Diaz-Meco MT (2011) p62 Is a Key Regulator of Nutrient Sensing in the mTORC1 Pathway. Mol. Cell 44, 134– 146. 21981924 PMC3190169
  108. [119]Adamik J, Silbermann R, Marino S, Sun Q, Anderson JL, Zhou D, Xie X-Q, Roodman GD, and Galson DL (2018) XRK3F2 Inhibition of p62-ZZ Domain Signaling Rescues Myeloma-Induced GFI1-Driven Epigenetic Repression of the Runx2 Gene in Pre-osteoblasts to Overcome Differentiation Suppression. Front. Endocrinol. 9, 344. PMC6033965 30008697
  109. [120]Teramachi J, Silbermann R, Yang P, Zhao W, Mohammad KS, Guo J, Anderson JL, Zhou D, Feng R, Myint KZ, Maertz N, Beumer JH, Eiseman JL, Windle JJ, Xie XQ, Roodman GD, and Kurihara N (2016) Blocking the ZZ domain of sequestosome1/p62 suppresses myeloma growth and osteoclast formation in vitro and induces dramatic bone formation in myeloma-bearing bones in vivo. Leukemia 30, 390. 26286116 PMC4740189
  110. [123]Yoo YD, Mun SR, Ji CH, Sung KW, Kang KY, Heo AJ, Lee SH, An JY, Hwang J, Xie X-Q, Ciechanover A, Kim BY, and Kwon YT (2018) N-terminal arginylation generates a bimodal degron that modulates autophagic proteolysis. Proc. Natl. Acad. Sci. U. S. A. 115, E2716– E2724. 29507222 PMC5866579
  111. [124]Cha-Molstad H, Lee SH, Kim JG, Sung KW, Hwang J, Shim SM, Ganipisetti S, McGuire T, Mook-Jung I, Ciechanover A, Xie X-Q, Kim BY, and Kwon YT (2018) Regulation of autophagic proteolysis by the N-recognin SQSTM1/p62 of the N-end rule pathway. Autophagy 14, 359– 361. 29261001 PMC5902234
  112. [125]Cha-Molstad H, Yu JE, Feng Z, Lee SH, Kim JG, Yang P, Han B, Sung KW, Yoo YD, Hwang J, McGuire T, Shim SM, Song HD, Ganipisetti S, Wang N, Jang JM, Lee MJ, Kim SJ, Lee KH, Hong JT, Ciechanover A, Mook-Jung I, Kim KP, Xie X-Q, Kwon YT, and Kim BY (2017) p62/SQSTM1/Sequestosome-1 is an N-recognin of the N-end rule pathway which modulates autophagosome biogenesis. Nat. Commun. 8, 102. 28740232 PMC5524641
  113. [126]Jin Z, Li Y, Pitti R, Lawrence D, Pham VC, Lill JR, and Ashkenazi A (2009) Cullin3-based polyubiquitination and p62-dependent aggregation of caspase-8 mediate extrinsic apoptosis signaling. Cell 137, 721– 735. 19427028
  114. [127]Wooten MW, Seibenhener ML, Mamidipudi V, Diaz-Meco MT, Barker PA, and Moscat J (2001) The atypical protein kinase C-interacting protein p62 is a scaffold for NF-κB activation by nerve growth factor. J. Biol. Chem. 276, 7709– 7712. 11244088
  115. [128]Geetha T, Jiang J, and Wooten MW (2005) Lysine 63 polyubiquitination of the nerve growth factor receptor TrkA directs internalization and signaling. Mol. Cell 20, 301– 312. 16246731
  116. [129]Wooten MW, Geetha T, Seibenhener ML, Babu JR, Diaz-Meco MT, and Moscat J (2005) The p62 scaffold regulates nerve growth factor-induced NF-κB activation by influencing TRAF6 polyubiquitination. J. Biol. Chem. 280, 35625– 35629. 16079148
  117. [130]Zheng C, Geetha T, Gearing M, and Ramesh Babu J (2015) Amyloid β abrogated TrkA ubiquitination in PC12 cells analogous to Alzheimer’s disease. J. Neurochem. 133, 919– 925. 25708205
  118. [131]Coulson E, May L, Sykes A, and Hamlin A (2009) The role of the p75 neurotrophin receptor in cholinergic dysfunction in Alzheimer’s disease. Neuroscientist 15, 317. 19458382
  119. [133]Komatsu M, Kurokawa H, Waguri S, Taguchi K, Kobayashi A, Ichimura Y, Sou Y-S, Ueno I, Sakamoto A, Tong KI, Kim M, Nishito Y, Iemura S. i., Natsume T, Ueno T, Kominami E, Motohashi H, Tanaka K, and Yamamoto M (2010) The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat. Cell Biol. 12, 213. 20173742
  120. [134]Jiang T, Harder B, Rojo de la Vega M, Wong PK, Chapman E, and Zhang DD (2015) p62 links autophagy and Nrf2 signaling. Free Radical Biol. Med. 88, 199– 204. 26117325 PMC4628872
  121. [135]Ichimura Y, and Komatsu M (2018) Activation of p62/SQSTM1–Keap1–Nuclear Factor Erythroid 2-Related Factor 2 Pathway in Cancer. Front. Oncol. 8, 210. 29930914 PMC5999793
  122. [136]Inami Y, Waguri S, Sakamoto A, Kouno T, Nakada K, Hino O, Watanabe S, Ando J, Iwadate M, Yamamoto M, Lee M-S, Tanaka K, and Komatsu M (2011) Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells. J. Cell Biol. 193, 275. 21482715 PMC3080263
  123. [137]Lippai M, and Low P (2014) The Role of the Selective Adaptor p62 and Ubiquitin-Like Proteins in Autophagy. BioMed Res. Int. 2014, 11. PMC4075091 25013806
  124. [138]Kanninen K, Heikkinen R, Malm T, Rolova T, Kuhmonen S, Leinonen H, Ylä-Herttuala S, Tanila H, Levonen A-L, Koistinaho M, and Koistinaho J (2009) Intrahippocampal injection of a lentiviral vector expressing Nrf2 improves spatial learning in a mouse model of Alzheimer’s disease. Proc. Natl. Acad. Sci. U. S.A. 106, 16505– 16510. 19805328 PMC2752553
  125. [139]Liddell J (2017) Are Astrocytes the Predominant Cell Type for Activation of Nrf2 in Aging and Neurodegeneration? Antioxidants 6, 65. PMC5618093 28820437
  126. [140]Rusten TE, and Stenmark H (2010) p62, an autophagy hero or culprit? Nat. Cell Biol. 12, 207. 20190829
  127. [141]Wei W, Li M, Wang J, Nie F, and Li L (2012) The E3 Ubiquitin Ligase ITCH Negatively Regulates Canonical Wnt Signaling by Targeting Dishevelled Protein. Mol. Cell. Biol. 32, 3903– 3912. 22826439 PMC3457526
  128. [142]Rechsteiner M, and Rogers SW (1996) PEST sequences and regulation by proteolysis. Trends Biochem. Sci. 21, 267– 271. 8755249
  129. [143]Rosenberg T, Gal-Ben-Ari S, Dieterich DC, Kreutz MR, Ziv NE, Gundelfinger ED, and Rosenblum K (2014) The roles of protein expression in synaptic plasticity and memory consolidation. Front. Mol. Neurosci. 7, 86. 25429258 PMC4228929
  130. [144]Liu WJ, Ye L, Huang WF, Guo LJ, Xu ZG, Wu HL, Yang C, and Liu HF (2016) p62 links the autophagy pathway and the ubiqutin–proteasome system upon ubiquitinated protein degradation. Cell. Mol. Biol. Lett. 21, 29. 28536631 PMC5415757
  131. [145]Lippai M, and Lőw P (2014) The Role of the Selective Adaptor p62 and Ubiquitin-Like Proteins in Autophagy. BioMed Res. Int. 2014, 832704. 25013806 PMC4075091
  132. [146]Nezis IP, and Stenmark H (2012) p62 at the Interface of Autophagy, Oxidative Stress Signaling, and Cancer. Antioxid. Redox Signaling 17, 786– 793. 22074114
  133. [147]Geetha T, Vishwaprakash N, Sycheva M, and Babu JR (2012) Sequestosome 1/p62: across diseases. Biomarkers 17, 99– 103. 22296116
  134. [148]Riley BE, Kaiser SE, Shaler TA, Ng ACY, Hara T, Hipp MS, Lage K, Xavier RJ, Ryu K-Y, Taguchi K, Yamamoto M, Tanaka K, Mizushima N, Komatsu M, and Kopito RR (2010) Ubiquitin accumulation in autophagy-deficient mice is dependent on the Nrf2-mediated stress response pathway: a potential role for protein aggregation in autophagic substrate selection. J. Cell Biol. 191, 537– 552. 21041446 PMC3003313
  135. [149]Wooten MW, Geetha T, Babu JR, Seibenhener ML, Peng J, Cox N, Diaz-Meco M-T, and Moscat J (2008) Essential role of sequestosome 1/p62 in regulating accumulation of Lys63-ubiquitinated proteins. J. Biol. Chem. 283, 6783– 6789. 18174161
  136. [150]Okamoto K, Hirai S, Yamazaki T, Sun X, and Nakazato Y (1991) New ubiquitin-positive intraneuronal inclusions in the extra-motor cortices in patients with amyotrophic lateral sclerosis. Neurosci. Lett. 129, 233– 236. 1660578
  137. [151]Nakano T, Nakaso K, Nakashima K, and Ohama E (2004) Expression of ubiquitin-binding protein p62 in ubiquitin-immunoreactive intraneuronal inclusions in amyotrophic lateral sclerosis with dementia: analysis of five autopsy cases with broad clinicopathological spectrum. Acta Neuropathol. 107, 359– 364. 14762676
  138. [152]Fecto F, Yan J, Vemula SP, Liu E, Yang Y, Chen W, Zheng JG, Shi Y, Siddique N, and Arrat H (2011) SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis. Arch. Neurol. 68, 1440– 1446. 22084127
  139. [153]Teyssou E, Takeda T, Lebon V, Boillée S, Doukouré B, Bataillon G, Sazdovitch V, Cazeneuve C, Meininger V, LeGuern E, Salachas F, Seilhean D, and Millecamps S (2013) Mutations in SQSTM1 encoding p62 in amyotrophic lateral sclerosis: genetics and neuropathology. Acta Neuropathol. 125, 511– 522. 23417734
  140. [154]Kwok CT, Morris A, and de Belleroche JS (2014) Sequestosome-1 (SQSTM1) sequence variants in ALS cases in the UK: prevalence and coexistence of SQSTM1 mutations in ALS kindred with PDB. Eur. J. Hum. Genet. 22, 492. 23942205 PMC3953910
  141. [155]Gal J, Strom AL, Kilty R, Zhang F, and Zhu H (2007) p62 accumulates and enhances aggregate formation in model systems of familial amyotrophic lateral sclerosis. J. Biol. Chem. 282, 11068– 11077. 17296612
  142. [156]Gal J, Ström AL, Kwinter DM, Kilty R, Zhang J, Shi P, Fu W, Wooten MW, and Zhu H (2009) Sequestosome 1/p62 links familial ALS mutant SOD1 to LC3 via an ubiquitin independent mechanism. J. Neurochem. 111, 1062– 1073. 19765191 PMC2766427
  143. [158]Ramesh N, and Pandey UB (2017) Autophagy Dysregulation in ALS: When Protein Aggregates Get Out of Hand. Front. Mol. Neurosci. 10, 263. 28878620 PMC5572252
  144. [159]Panegyres PK, and Frencham K (2007) Course and Causes of Suspected Dementia in Young Adults: A Longitudinal Study. American Journal of Alzheimer’s Disease Other Dementias 22, 48– 56. PMC10697200 17534002
  145. [161]Mohandas E, and Rajmohan V (2009) Frontotemporal dementia: An updated overview. Indian journal of psychiatry 51, S65– S69. 21416021 PMC3038533
  146. [162]Pikkarainen M, Hartikainen P, and Alafuzoff I (2008) Neuropathologic features of frontotemporal lobar degeneration with ubiquitin-positive inclusions visualized with ubiquitin-binding protein p62 immunohistochemistry. J. Neuropathol. Exp. Neurol. 67, 280– 298. 18379439
  147. [163]Abrahams S, Goldstein LH, Simmons A, Brammer M, Williams SC, Giampietro V, and Leigh PN (2004) Word retrieval in amyotrophic lateral sclerosis: a functional magnetic resonance imaging study. Brain 127, 1507– 1517. 15163610
  148. [164]Mackenzie IR, and Feldman HH (2005) Ubiquitin immunohistochemistry suggests classic motor neuron disease, motor neuron disease with dementia, and frontotemporal dementia of the motor neuron disease type represent a clinicopathologic spectrum. J. Neuropathol. Exp. Neurol. 64, 730– 739. 16106222
  149. [165]Lipton AM, White CL 3rd, and Bigio EH (2004) Frontotemporal lobar degeneration with motor neuron disease-type inclusions predominates in 76 cases of frontotemporal degeneration. Acta Neuropathol. 108, 379– 385. 15351890
  150. [166]Ferrari R, Kapogiannis D, Huey ED, and Momeni P (2011) FTD and ALS: a tale of two diseases. Curr. Alzheimer Res. 8, 273– 294. 21222600 PMC3801195
  151. [167]Liscic RM, Grinberg LT, Zidar J, Gitcho MA, and Cairns NJ (2008) ALS and FTLD: two faces of TDP-43 proteinopathy. European Journal of Neurology 15, 772– 780. 18684309 PMC2801606
  152. [169]Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, and Lee VM (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science (Washington, DC, U. S.) 314, 130– 133. 17023659
  153. [171]Mori K, Weng S-M, Arzberger T, May S, Rentzsch K, Kremmer E, Schmid B, Kretzschmar HA, Cruts M, Van Broeckhoven C, (2013) The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science (Washington, DCU. S.) 339, 1335– 1338. 23393093
  154. [172]King A, Al-Sarraj S, Troakes C, Smith BN, Maekawa S, Iovino M, Spillantini MG, and Shaw CE (2013) Mixed tau, TDP-43 and p62 pathology in FTLD associated with a C9ORF72 repeat expansion and p. Ala239Thr MAPT (tau) variant. Acta Neuropathol. 125, 303– 310. 23053136
  155. [173]Goode A, Butler K, Long J, Cavey J, Scott D, Shaw B, Sollenberger J, Gell C, Johansen T, Oldham NJ, Searle MS, and Layfield R (2016) Defective recognition of LC3B by mutant SQSTM1/p62 implicates impairment of autophagy as a pathogenic mechanism in ALS-FTLD. Autophagy 12, 1094– 1104. 27158844 PMC4990988
  156. [174]Goode A, Rea S, Sultana M, Shaw B, Searle MS, and Layfield R (2016) ALS-FTLD associated mutations of SQSTM1 impact on Keap1-Nrf2 signalling. Mol. Cell. Neurosci. 76, 52– 58. 27554286 PMC5062946
  157. [175]Castillo K, Nassif M, Valenzuela V, Rojas F, Matus S, Mercado G, Court FA, van Zundert B, and Hetz C (2013) Trehalose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneurons. Autophagy 9, 1308– 1320. 23851366
  158. [176]Zhang X, Chen S, Song L, Tang Y, Shen Y, Jia L, and Le W (2014) MTOR-independent, autophagic enhancer trehalose prolongs motor neuron survival and ameliorates the autophagic flux defect in a mouse model of amyotrophic lateral sclerosis. Autophagy 10, 588– 602. 24441414 PMC4091147
  159. [177]Helferich AM, Ruf WP, Grozdanov V, Freischmidt A, Feiler MS, Zondler L, Ludolph AC, McLean PJ, Weishaupt JH, and Danzer KM (2015) alpha-synuclein interacts with SOD1 and promotes its oligomerization. Mol. Neurodegener. 10, 66. 26643113 PMC4672499
  160. [178]Majbour NK, Vaikath NN, van Dijk KD, Ardah MT, Varghese S, Vesterager LB, Montezinho LP, Poole S, Safieh-Garabedian B, Tokuda T, Teunissen CE, Berendse HW, van de Berg WD, and El-Agnaf OM (2016) Oligomeric and phosphorylated alpha-synuclein as potential CSF biomarkers for Parkinson’s disease. Mol. Neurodegener. 11, 7. 26782965 PMC4717559
  161. [179]Cha SH, Choi YR, Heo CH, Kang SJ, Joe EH, Jou I, Kim HM, and Park SM (2015) Loss of parkin promotes lipid rafts-dependent endocytosis through accumulating caveolin-1: implications for Parkinson’s disease. Mol. Neurodegener. 10, 63. 26627850 PMC4666086
  162. [180]Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, and Shimizu N (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392, 605– 608. 9560156
  163. [182]Leroy E, Boyer R, Auburger G, Leube B, Ulm G, Mezey E, Harta G, Brownstein MJ, Jonnalagada S, Chernova T, Dehejia A, Lavedan C, Gasser T, Steinbach PJ, Wilkinson KD, and Polymeropoulos MH (1998) The ubiquitin pathway in Parkinson’s disease. Nature 395, 451– 452. 9774100
  164. [183]Saha S, Ash PE, Gowda V, Liu L, Shirihai O, and Wolozin B (2015) Mutations in LRRK2 potentiate age-related impairment of autophagic flux. Mol. Neurodegener. 10, 26. 26159606 PMC4702340
  165. [184]Narendra D, Kane LA, Hauser DN, Fearnley IM, and Youle RJ (2010) p62/SQSTM1 is required for Parkin-induced mitochondrial clustering but not mitophagy; VDAC1 is dispensable for both. Autophagy 6, 1090– 1106. 20890124 PMC3359490
  166. [187]Song P, Li S, Wu H, Gao R, Rao G, Wang D, Chen Z, Ma B, Wang H, Sui N, Deng H, Zhang Z, Tang T, Tan Z, Han Z, Lu T, Zhu Y, and Chen Q (2016) Parkin promotes proteasomal degradation of p62: implication of selective vulnerability of neuronal cells in the pathogenesis of Parkinson’s disease. Protein Cell 7, 114– 129. 26746706 PMC4742389
  167. [188]Kalogeropulou AF, Zhao J, Bolliger MF, Memou A, Narasimha S, Molitor TP, Wilson WH, Rideout HJ, and Nichols RJ (2018) p62/SQSTM1 is a novel Leucine Rich Repeat Kinase 2(LRRK2) substrate that enhances neuronal toxicity. Biochem. J. 475, 1271. 29519959
  168. [189]Park S, Han S, Choi I, Kim B, Park SP, Joe E-H, and Suh YH (2016) Interplay between Leucine-Rich Repeat Kinase 2 (LRRK2) and p62/SQSTM-1 in Selective Autophagy. PLoS One 11, No. e0163029. PMC5025236 27631370
  169. [190]Braak H, Thal DR, and Del Tredici K (2011) Nerve cells immunoreactive for p62 in select hypothalamic and brainstem nuclei of controls and Parkinson’s disease cases. J. Neural Transm (Vienna) 118, 809– 819. 21052746
  170. [192]Kuusisto E, Salminen A, and Alafuzoff I (2001) Ubiquitin-binding protein p62 is present in neuronal and glial inclusions in human tauopathies and synucleinopathies. NeuroReport 12, 2085– 2090. 11447312
  171. [193]Kuusisto E, Parkkinen L, and Alafuzoff I (2003) Morphogenesis of Lewy Bodies: Dissimilar Incorporation of α-Synuclein, Ubiquitin, and p62. J. Neuropathol. Exp. Neurol. 62, 1241– 1253. 14692700
  172. [194]Nakaso K, Yoshimoto Y, Nakano T, Takeshima T, Fukuhara Y, Yasui K, Araga S, Yanagawa T, Ishii T, and Nakashima K (2004) Transcriptional activation of p62/A170/ZIP during the formation of the aggregates: possible mechanisms and the role in Lewy body formation in Parkinson’s disease. Brain Res. 1012, 42– 51. 15158159
  173. [195]Kremer B, Goldberg P, Andrew SE, Theilmann J, Telenius H, Zeisler J, Squitieri F, Lin B, Bassett A, Almqvist E, Bird TD, and Hayden MR (1994) A Worldwide Study of the Huntington’s Disease Mutation: The Sensitivity and Specificity of Measuring CAG Repeats. N. Engl J. Med. 330, 1401– 1406. 8159192
  174. [197]Wold MS, Lim J, Lachance V, Deng Z, and Yue Z (2016) ULK1-mediated phosphorylation of ATG14 promotes autophagy and is impaired in Huntington’s disease models. Mol. Neurodegener. 11, 76. 27938392 PMC5148922
  175. [198]Rué L, López-Soop G, Gelpi E, Martínez-Vicente M, Alberch J, and Pérez-Navarro E (2013) Brain region- and age-dependent dysregulation of p62 and NBR1 in a mouse model of Huntington’s disease. Neurobiol Dis. 52, 219– 228. 23295856
  176. [199]Bjørkøy G, Lamark T, Brech A, Outzen H, Perander M, Overvatn A, Stenmark H, and Johansen T (2005) p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J. Cell Biol. 171, 603– 614. 16286508 PMC2171557
  177. [200]Kurosawa M, Matsumoto G, Kino Y, Okuno M, Kurosawa-Yamada M, Washizu C, Taniguchi H, Nakaso K, Yanagawa T, Warabi E, Shimogori T, Sakurai T, Hattori N, and Nukina N (2015) Depletion of p62 reduces nuclear inclusions and paradoxically ameliorates disease phenotypes in Huntington’s model mice. Hum. Mol. Genet. 24, 1092– 1105. 25305080
  178. [201]Lee H, Ahn H-H, Lee W, Oh Y, Choi H, Shim SM, Shin J, and Jung Y-K (2016) ENC1Modulates the Aggregation and Neurotoxicity of Mutant Huntingtin Through p62 Under ER Stress. Mol. Neurobiol. 53, 6620– 6634. 26637326
  179. [202]Huang N, Erie C, Lu ML, and Wei J (2018) Aberrant subcellular localization of SQSTM1/p62 contributes to increased vulnerability to proteotoxic stress recovery in Huntington’s disease. Mol. Cell. Neurosci. 88, 43– 52. 29246658 PMC5893379
  180. [203]Vadlamudi RK, and Shin J (1998) Genomic structure and promoter analysis of the p62 gene encoding a non-proteasomal multiubiquitin chain binding protein. FEBS Lett. 435, 138– 142. 9762895
  181. [204]Pastorcic M, and Das HK (2003) Ets transcription factors ER81 and Elk1 regulate the transcription of the human presenilin 1 gene promoter. Mol. Brain Res. 113, 57– 66. 12750007
  182. [205]Caccamo A, Ferreira E, Branca C, and Oddo S (2017) p62 improves AD-like pathology by increasing autophagy. Mol. Psychiatry 22, 865– 873. 27573878 PMC5479312
  183. [206]Tanji K, Miki Y, Ozaki T, Maruyama A, Yoshida H, Mimura J, Matsumiya T, Mori F, Imaizumi T, Itoh K, (2014) Phosphorylation of serine 349 of p62 in Alzheimer’s disease brain. Acta neuropathologica communications 2, 1. 24886973 PMC4035093
  184. [207]Zheng X, Wang W, Liu R, Huang H, Zhang R, and Sun L (2012) Effect ofp62 on tau hyperphosphorylation in a rat model of Alzheimer’s disease. Neural Regeneration Research 7, 1304– 1311. 25657660 PMC4308800

Cited by

Sorted by citations

Authors
Ma, S., Attarwala, I. Y., & Xie, X.-Q.
Affiliations
  • University of Pittsburgh (US)
  • ID4Pharma LLC, Bridgeville, Pennsylvania 15017, United States
Corresponding author
Xie, Xiang-Qun
ORCID
Xie, Xiang-Qun
Venue
ACS Chemical Neuroscience
Publisher
American Chemical Society (ACS)
Published
2019-01-18
Volume
10
Issue
5
Pages
2094-2114
ISSN
1948-7193 (ISSN-L)
DOI
10.1021/acschemneuro.8b00516
PMC
PMC6712989
OpenAlex
W2910978113
Cited by
185
References
18
Citations by year
2026: 19 · 2025: 34 · 2024: 30 · 2023: 33 · 2022: 21 · 2021: 27 · 2020: 18 · 2019: 2
FWCI
2.52
Type
journal article
Language
en
Open access
Licence
Locations
  • ACS Chemical Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • U.S. Department of Defense (W81XWH-16-1-0490)
  • National Institute on Drug Abuse (P30 DA035778A1)
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords
p62, neurodegenerative diseases, macroautophagy, autophagy modulators, protein aggregation, proteostasis, autophagosomes, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, frontotemporal lobar degeneration, therapeutic target
MeSH terms
Sequestosome-1 Protein, Animals, Autophagy, Brain, Humans, Signal Transduction, Neurodegenerative Diseases

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review