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The Autophagy–Lysosomal Pathway in Neurodegeneration: A TFEB Perspective
Open accessAbstract
The autophagy-lysosomal pathway (ALP) is involved in the degradation of long-lived proteins. Deficits in the ALP result in protein aggregation, the generation of toxic protein species, and accumulation of dysfunctional organelles, which are hallmarks of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and prion disease. Decades of research have therefore focused on enhancing the ALP in neurodegenerative diseases. More recently, transcription factor EB (TFEB), a major regulator of autophagy and lysosomal biogenesis, has emerged as a leading factor in addressing disease pathology. We review the regulation of the ALP and TFEB and their impact on neurodegenerative diseases. We also offer our perspective on the complex role of autophagy and TFEB in disease pathogenesis and its therapeutic implications through the examination of prion disease.
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“TFE3 or TFEB upregulation or activation through pharmacological inhibition of mTORC1 can trigger clearance of excess α-synuclein and halt the progression of neurotoxicity17–22.”
From PDCD4 triggers α-synuclein accumulation and motor deficits via co-suppressing TFE3 and TFEB translation in a model of Parkinson’s disease (2024) · cites this paper as [20]
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“Molecular and histopathologic analyses of patient tissues demonstrate mislocalized or accumulated autophagy machinery, pathogenic mutations underlying familial neurodegenerative diseases disable known autophagy-related factors, and genetically ablating autophagy effectors produce neurodegeneration in cell and animal model systems [74–81], supporting a role for autophagy dysfunction in the devel”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [79]
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Metadata
- Authors
- Martini-Stoica, H., Xu, Y., Ballabio, A., & Zheng, H.
- Affiliations
- Baylor College of Medicine (US)
- Corresponding author
- Zheng, Hui
- Venue
- Trends in Neurosciences
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 39
- Issue
- 4
- Pages
- 221-234
- ISSN
- 0166-2236 (ISSN-L)
- PMC
- PMC4928589
- OpenAlex
- W2293027573
- Cited by
- 436
- References
- 127
- Citations by year
- 2026: 38 · 2025: 41 · 2024: 46 · 2023: 65 · 2022: 48 · 2021: 53 · 2020: 43 · 2019: 34 · 2018: 27 · 2017: 31 · 2016: 10
- FWCI
- 4.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Trends in Neurosciences (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (RF1AG020670, F30AG050412, R01AG020670)
- National Institute of Neurological Disorders and Stroke (R01NS076117, RF1NS093652, R01NS078072, R01NS093652)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Keywords
- autophagy-lysosome pathway, TFEB, neurodegenerative diseases, lysosomal biogenesis, protein aggregation, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion disease, autophagy regulation, therapeutic target
- MeSH terms
- Animals, Autophagy, Brain, Humans, Lysosomes, Nerve Degeneration, Neurodegenerative Diseases, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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