Lysosomal response in relation to α-synuclein pathology differs between Parkinson's disease and multiple system atrophy

Neurobiology of Disease

Lajos Laszlo¹  Kinga Molnar¹  Gina Puska¹  Walter Pirker²  Günther Regelsberger³  Mirjam I. Lutz³  Gerda Ricken³  Gabor G. Kovacs³ 

[1] Department of Anatomy, Cell and Developmental Biology, Eötvös Lorand University, Budapest, Hungary;Department of Neurology, Wilhelminenspital, Vienna, Austria;Institute of Neurology, Medical University of Vienna, Vienna, Austria;

关键词: α-Synuclein;    Cathepsin D;    Endosome;    Lysosome;    Multiple system atrophy;    Neurodegeneration;   

DOI  :  

来源: DOAJ

【 摘 要 】

Intracellular deposition of pathologically altered α-synuclein mostly in neurons characterises Parkinson's disease (PD), while its accumulation predominantly in oligodendrocytes is a feature of multiple system atrophy (MSA). Recently a prion-like spreading of pathologic α-synuclein has been suggested to play a role in the pathogenesis of PD and MSA. This implicates a role of protein processing systems, including lysosomes, supported also by genetic studies in PD. However, particularly for MSA, the mechanism of cell-to-cell propagation of α-synuclein is yet not fully understood. To evaluate the significance of lysosomal response, we systematically compared differently affected neuronal populations in PD, MSA, and non-diseased brains using morphometric immunohistochemistry (cathepsin D), double immunolabelling (cathepsin D/α-synuclein) laser confocal microscopy, and immunogold electron microscopy for the disease associated α-synuclein. We found that i) irrespective of the presence of neuronal inclusions, the volume density of cathepsin D immunoreactivity significantly increases in affected neurons of the pontine base in MSA brains; ii) volume density of cathepsin D immunoreactivity increases in nigral neurons in PD without inclusions and with non-ubiquitinated pre-aggregates of α-synuclein, but not in neurons with Lewy bodies; iii) cathepsin D immunoreactivity frequently colocalises with α-synuclein pre-aggregates in nigral neurons in PD; iv) ultrastructural observations confirm disease-associated α-synuclein in neuronal and astrocytic lysosomes in PD; v) lysosome-associated α-synuclein is observed in astroglia and rarely in oligodendroglia and in neurons in MSA. Our observations support a crucial role for the neuronal endosomal-lysosomal system in the processing of α-synuclein in PD. We suggest a distinct contribution of lysosomes to the pathogenesis of MSA, including the possibility of oligodendroglial and eventually neuronal uptake of exogenous α-synuclein in MSA.

【 授权许可】

Unknown