Dysfunction of the autophagy/lysosomal degradation pathway is a shared feature of the genetic synucleinopathies
Claudia Manzoni,Patrick A. Lewis +1 more
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TLDR
It is proposed that the genetic forms of Parkinson's disease largely associated with α‐synuclein‐positive neuropathology (SNCA, LRRK2, and GBA) are brought together by involvement in the autophagy/lysosomal pathway and that this represents a unifying pathway to disease in these cases.Abstract:
The past decade has witnessed huge advances in our understanding of the genetics underlying Parkinson's disease. Identifying commonalities in the biological function of genes linked to Parkinson's provides an opportunity to elucidate pathways that lead to neuronal degeneration and eventually to disease. We propose that the genetic forms of Parkinson's disease largely associated with α-synuclein-positive neuropathology (SNCA, LRRK2, and GBA) are brought together by involvement in the autophagy/lysosomal pathway and that this represents a unifying pathway to disease in these cases.read more
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Regulation of autophagy by mTOR-dependent and mTOR-independent pathways: autophagy dysfunction in neurodegenerative diseases and therapeutic application of autophagy enhancers.
TL;DR: The present review describes the cellular signalling pathways regulating mammalian autophagy and highlights the potential therapeutic application of Autophagy inducers in neurodegenerative disorders.
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Modeling G2019S-LRRK2 Sporadic Parkinson's Disease in 3D Midbrain Organoids.
Hongwon Kim,Hyeok Ju Park,Hwan Choi,Yujung Chang,Hanseul Park,Jaein Shin,Junyeop Kim,Christopher J. Lengner,Yong Kyu Lee,Jongpil Kim +9 more
TL;DR: Analysis of the protein-protein interaction network in mutant organoids revealed that TXNIP, a thiol-oxidoreductase, is functionally important in the development of LRRK2-associated Parkinson's disease in a 3D environment.
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Autophagy and Alpha-Synuclein: Relevance to Parkinson's Disease and Related Synucleopathies
TL;DR: Findings related to the inter‐relationship between alpha‐synuclein and lysosomal proteolytic pathways are summarized, focusing especially on recent experimental strategies based on the manipulation of the autophagy lysOSomal pathway to counteract alpha‐ synuclein‐mediated neurotoxicity in vivo.
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Pathogenesis of synaptic degeneration in Alzheimer's disease and Lewy body disease.
Cassia R. Overk,Eliezer Masliah +1 more
TL;DR: Understanding the molecular and cellular mechanisms of synaptic degeneration is crucial toward developing specific biomarkers and new therapies targeting the synaptic apparatus of vulnerable neurons in Alzheimer's disease and Parkinson's disease.
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Propagation of alpha-synuclein pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies.
TL;DR: Revised models of αS amyloidogenic precursors termed “seeds” were experimentally injected into the brain or peripheral nervous system of animals to better understand the mechanisms underlying the variable progression of Lewy body diseases.
References
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Mutation in the α-synuclein gene identified in families with Parkinson's disease
Mihael H. Polymeropoulos,Christian Lavedan,Elisabeth Leroy,Susan E. Ide,Anindya Dehejia,Amalia Dutra,Brian L. Pike,Holly Root,Jeffrey Rubenstein,Rebecca Boyer,Edward S. Stenroos,Settara C. Chandrasekharappa,Aglaia Athanassiadou,Theodore Papapetropoulos,William G. Johnson,Alice Lazzarini,Roger C. Duvoisin,Giuseppe Di Iorio,Lawrence I. Golbe,Robert L. Nussbaum +19 more
TL;DR: A mutation was identified in the α-synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity, in the Italian kindred and in three unrelated families of Greek origin with autosomal dominant inheritance for the PD phenotype.
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Alpha-synuclein in Lewy bodies.
Maria Grazia Spillantini,Marie L. Schmidt,Virginia M.-Y. Lee,John Q. Trojanowski,Ross Jakes,Michel Goedert +5 more
TL;DR: Strong staining of Lewy bodies from idiopathic Parkinson's disease with antibodies for α-synuclein, a presynaptic protein of unknown function which is mutated in some familial cases of the disease, indicates that the LewY bodies from these two diseases may have identical compositions.
Journal ArticleDOI
Mutations in LRRK2 Cause Autosomal-Dominant Parkinsonism with Pleomorphic Pathology
Alexander Zimprich,Alexander Zimprich,Saskia Biskup,Petra Leitner,Peter Lichtner,Matthew J. Farrer,Sarah Lincoln,Jennifer M. Kachergus,Mary M. Hulihan,Ryan J. Uitti,Donald B. Calne,A. Jon Stoessl,Ronald F. Pfeiffer,Nadja Patenge,Iria Carballo Carbajal,Peter Vieregge,Friedrich Asmus,Bertram Müller-Myhsok,Dennis W. Dickson,Thomas Meitinger,Tim M. Strom,Zbigniew K. Wszolek,Thomas Gasser +22 more
TL;DR: High-resolution recombination mapping and candidate gene sequencing in 46 families found six disease-segregating mutations in a gene encoding a large, multifunctional protein, LRRK2 (leucine-rich repeat kinase 2), which may be central to the pathogenesis of several major neurodegenerative disorders associated with parkinsonism.
Journal ArticleDOI
Impaired degradation of mutant α-synuclein by chaperone-mediated autophagy
TL;DR: It is found that wild-type α-synuclein was selectively translocated into lysosomes for degradation by the chaperone-mediated autophagy pathway, which may underlie the toxic gain-of-function by the A53T and A30P mutants.
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