Alpha-Synuclein and LRRK2 in Synaptic Autophagy: Linking Early Dysfunction to Late-Stage Pathology in Parkinson's Disease

被引:17
|
作者
Lamonaca, Giulia
Volta, Mattia
机构
[1] Institute for Biomedicine, Eurac Research-Affiliated Institute of the University of Lübeck, Bolzano
关键词
LRRK2; autophagy; Parkinson's disease; alpha-synuclein; synaptic transmission; neuropathology; MEDIUM SPINY NEURONS; KINASE; 2; LRRK2; VESICLE ENDOCYTOSIS; NEURODEGENERATIVE PATHOLOGY; FAMILIAL PARKINSONISM; REGULATES AUTOPHAGY; SAC1; DOMAIN; LEWY BODY; MUTATIONS; MODEL;
D O I
10.3390/cells9051115
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
The lack of effective disease-modifying strategies is the major unmet clinical need in Parkinson's disease. Several experimental approaches have attempted to validate cellular targets and processes. Of these, autophagy has received considerable attention in the last 20 years due to its involvement in the clearance of pathologic protein aggregates and maintenance of neuronal homeostasis. However, this strategy mainly addresses a very late stage of the disease, when neuropathology and neurodegeneration have likely "tipped over the edge" and disease modification is extremely difficult. Very recently, autophagy has been demonstrated to modulate synaptic activity, a process distinct from its catabolic function. Abnormalities in synaptic transmission are an early event in neurodegeneration with Leucine-Rich Repeat Kinase 2 (LRRK2) and alpha-synuclein strongly implicated. In this review, we analyzed these processes separately and then discussed the unification of these biomolecular fields with the aim of reconstructing a potential "molecular timeline" of disease onset and progression. We postulate that the elucidation of these pathogenic mechanisms will form a critical basis for the design of novel, effective disease-modifying therapies that could be applied early in the disease process.
引用
收藏
页数:21
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