TY - JOUR
T1 - Alterations in lysosomal and proteasomal markers in Parkinson's disease
T2 - Relationship to alpha-synuclein inclusions
AU - Chu, Yaping
AU - Dodiya, Hemraj
AU - Aebischer, Patrick
AU - Olanow, C. Warren
AU - Kordower, Jeffrey H.
PY - 2009/9
Y1 - 2009/9
N2 - We explored the relationship between ubiquitin proteasome system (UPS) and lysosomal markers and the formation of α-synuclein (α-syn) inclusions in nigral neurons in Parkinson disease (PD). Lysosome Associated Membrane Protein 1(LAMP1), Cathepsin D (CatD), and Heat Shock Protein73 (HSP73) immunoreactivity were significantly decreased within PD nigral neurons when compared to age-matched controls. This decrease was significantly greater in nigral neurons that contained α-syn inclusions. Immunoreactivity for 20S proteasome was similarly reduced in PD nigral neurons, but only in cells that contained inclusions. In aged control brains, there is staining for α-syn protein, but it is non-aggregated and there is no difference in LAMP1, CatD, HSP73 or 20S proteasome immunoreactivity between α-syn positive or negative neuromelanin-laden nigral neurons. Targeting over-expression of mutant human α-syn in the rat substantia nigra using viral vectors revealed that lysosomal and proteasomal markers were significantly decreased in the neurons that displayed α-syn-ir inclusions. These findings suggest that α-syn aggregation is a key feature associated with decline of proteasome and lysosome and support the hypothesis that cell degeneration in PD involves proteosomal and lysosomal dysfunction, impaired protein clearance, and protein accumulation and aggregation leading to cell death.
AB - We explored the relationship between ubiquitin proteasome system (UPS) and lysosomal markers and the formation of α-synuclein (α-syn) inclusions in nigral neurons in Parkinson disease (PD). Lysosome Associated Membrane Protein 1(LAMP1), Cathepsin D (CatD), and Heat Shock Protein73 (HSP73) immunoreactivity were significantly decreased within PD nigral neurons when compared to age-matched controls. This decrease was significantly greater in nigral neurons that contained α-syn inclusions. Immunoreactivity for 20S proteasome was similarly reduced in PD nigral neurons, but only in cells that contained inclusions. In aged control brains, there is staining for α-syn protein, but it is non-aggregated and there is no difference in LAMP1, CatD, HSP73 or 20S proteasome immunoreactivity between α-syn positive or negative neuromelanin-laden nigral neurons. Targeting over-expression of mutant human α-syn in the rat substantia nigra using viral vectors revealed that lysosomal and proteasomal markers were significantly decreased in the neurons that displayed α-syn-ir inclusions. These findings suggest that α-syn aggregation is a key feature associated with decline of proteasome and lysosome and support the hypothesis that cell degeneration in PD involves proteosomal and lysosomal dysfunction, impaired protein clearance, and protein accumulation and aggregation leading to cell death.
KW - Alpha-synuclein
KW - Lysosome
KW - Parkinson's disease
KW - Proteasome
UR - http://www.scopus.com/inward/record.url?scp=68149123529&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=68149123529&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2009.05.023
DO - 10.1016/j.nbd.2009.05.023
M3 - Article
C2 - 19505575
AN - SCOPUS:68149123529
SN - 0969-9961
VL - 35
SP - 385
EP - 398
JO - Neurobiology of Disease
JF - Neurobiology of Disease
IS - 3
ER -