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Cited by 35Alzheimer's disease research and treatmentsParkinson's Disease Mechanisms and TreatmentsAmyotrophic Lateral Sclerosis Research

Mutations in α-synuclein, TDP-43 and tau prolong protein half-life through diminished degradation by lysosomal proteases

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Sampognaro, Paul J., Arya, Shruti, Knudsen, Giselle M., Gunderson, Emma L., Sandoval-Perez, Angelica, Hodul, Molly, Bowles, Kathryn, Craik, Charles S. +2 more·2023·Molecular Neurodegeneration
DOI 10.1186/s13024-023-00621-8PMC PMC10155372
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Abstract

Background: Autosomal dominant mutations in α-synuclein, TDP-43 and tau are thought to predispose to neurodegeneration by enhancing protein aggregation. While a subset of α-synuclein, TDP-43 and tau mutations has been shown to increase the structural propensity of these proteins toward self-association, rates of aggregation are also highly dependent on protein steady state concentrations, which are in large part regulated by their rates of lysosomal degradation. Previous studies have shown that lysosomal proteases operate precisely and not indiscriminately, cleaving their substrates at very specific linear amino acid sequences. With this knowledge, we hypothesized that certain coding mutations in α-synuclein, TDP-43 and tau may lead to increased protein steady state concentrations and eventual aggregation by an alternative mechanism, that is, through disrupting lysosomal protease cleavage recognition motifs and subsequently conferring protease resistance to these proteins. Results: To test this possibility, we first generated comprehensive proteolysis maps containing all of the potential lysosomal protease cleavage sites for α-synuclein, TDP-43 and tau. In silico analyses of these maps indicated that certain mutations would diminish cathepsin cleavage, a prediction we confirmed utilizing in vitro protease assays. We then validated these findings in cell models and induced neurons, demonstrating that mutant forms of α-synuclein, TDP-43 and tau are degraded less efficiently than wild type despite being imported into lysosomes at similar rates. Conclusions: Together, this study provides evidence that pathogenic mutations in the N-terminal domain of α-synuclein (G51D, A53T), low complexity domain of TDP-43 (A315T, Q331K, M337V) and R1 and R2 domains of tau (K257T, N279K, S305N) directly impair their own lysosomal degradation, altering protein homeostasis and increasing cellular protein concentrations by extending the degradation half-lives of these proteins. These results also point to novel, shared, alternative mechanism by which different forms of neurodegeneration, including synucleinopathies, TDP-43 proteinopathies and tauopathies, may arise. Importantly, they also provide a roadmap for how the upregulation of particular lysosomal proteases could be targeted as potential therapeutics for human neurodegenerative disease.

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  • TSC is recognized as a juvenile tauopathy.

    “Tubers isolated from infants with TSC1 mutations demonstrate hyperphosphorylated tau and thus it is recognized as a “juvenile tauopathy.”139”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [139]

    The References section lists a study titled “TSC1 loss increases risk for tauopathy,” which supports a connection between TSC1 loss and tauopathy. Our copy does not say that TSC is recognized as a juvenile tauopathy or report hyperphosphorylated tau in tubers from infants; the Results and Discussion passages concern tau degradation instead. No page numbers are available in our copy. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • Tubers isolated from infants with TSC1 mutations demonstrate hyperphosphorylated tau.

    “Tubers isolated from infants with TSC1 mutations demonstrate hyperphosphorylated tau and thus it is recognized as a “juvenile tauopathy.”139”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [139]

    The Results (Tau; page unavailable) examine lysosomal cleavage of tau, not tubers from infants. The References list a study on TSC1 loss and tauopathy, but our copy does not report hyperphosphorylated tau in infant tubers or describe TSC1-associated tubers as a juvenile tauopathy. Searches for infant tubers, TSC1, hyperphosphorylated tau, and juvenile tauopathy found no passage establishing the claim. (LLM, conf=0.76)

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Authors
Sampognaro, P. J., Arya, S., Knudsen, G. M., Gunderson, E. L., Sandoval-Perez, A., Hodul, M., Bowles, K., Craik, C. S., Jacobson, M. P., & Kao, A. W.
Affiliations
  • University of California, San Francisco (US)
  • UK Dementia Research Institute (GB)
Corresponding author
Kao, Aimee W.
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2023-05-02
Volume
18
Issue
1
Pages
29-29
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-023-00621-8
PMC
PMC10155372
OpenAlex
W4367693701
Cited by
35
References
5
Citations by year
2026: 13 · 2025: 10 · 2024: 10 · 2023: 2
FWCI
6.22
Type
journal article
Language
en
Update notices
correction (2023-05-30)
Open access
Licence
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institute of Neurological Disorders and Stroke (K08NS121519)
  • American Academy of Neurology (Richard Olney Clinician Scientist Development Award)
  • National Institutes of Health (U54 NS123746-01, RF1AG068125, R01NS095257, R01AG057342, R01AG059052, U54NS123985)
  • BrightFocus Foundation (A2021021S)
  • National Institute of Aging (R01AG059052)
  • Larry Berkelhammer Foundation
  • Paul G. Allen Family Foundation
  • Tau Consortium
  • Parkinson's Disease Foundation
  • Glenn Foundation for Aging Research
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
alpha-synuclein mutations, TDP-43 mutations, tau mutations, protease resistance, protein half-life, lysosomal degradation, protein aggregation, neurodegeneration, synucleinopathies, TDP-43 proteinopathy, tauopathy, low-complexity domains, N-terminal domain
MeSH terms
DNA-Binding Proteins, Half-Life, Humans, Lysosomes, Mutation, Peptide Hydrolases, tau Proteins, Neurodegenerative Diseases, alpha-Synuclein

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