Alterations in lysosomal and proteasomal markers in Parkinson's disease: relationship to alpha-synuclein inclusions.
We explored the relationship between ubiquitin proteasome system (UPS) and lysosomal markers and the formation of alpha-synuclein (alpha-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 alpha-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 alpha-syn protein, but it is non-aggregated and there is no difference in LAMP1, CatD, HSP73 or 20S proteasome immunoreactivity between alpha-syn positive or negative neuromelanin-laden nigral neurons. Targeting over-expression of mutant human alpha-syn in the rat substantia nigra using viral vectors revealed that lysosomal and proteasomal markers were significantly decreased in the neurons that displayed alpha-syn-ir inclusions. These findings suggest that alpha-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.
Chu
Yaping
Y
Department of Neurological Sciences, Rush University Medical Center, 1735 West Harrison Street, Chicago, IL 60612, USA.
Dodiya
Hemraj
H
Aebischer
Patrick
P
Olanow
C Warren
CW
Kordower
Jeffrey H
JH
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002402:Cathepsin D / Q000378:metabolism*; D005260:Female; D005822:Genetic Vectors; D050883:HSC70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D051907:Lysosomal Membrane Proteins / Q000378:metabolism*; D008297:Male; D008543:Melanins / Q000378:metabolism; D009154:Mutation; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*; D052118:Lysosomal-Associated Membrane Protein 1
D002402:Cathepsin D; D050883:HSC70 Heat-Shock Proteins; D051907:Lysosomal Membrane Proteins; D008543:Melanins; D046988:Proteasome Endopeptidase Complex; D051844:alpha-Synuclein; C494371:HSPA8 protein, human; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1; C014121:neuromelanin; C533922:CTSD protein, human