Dysfunction of protein homoeostasis has been implicated in the pathogenesis of a diverse array of neurodegenerative disorders. However, each neurodegenerative disease is characterized by the accumulation of particular proteins in select regions of the brain. It remains unclear how dysfunction of a ubiquitous protein degradation pathway results in distinct pathologies. α-Synuclein is a protein whose aggregation and oligomerization has been implicated in several diseases, including Parkinson’s disease (PD). Herein, we investigated regionally selective alterations in α-synuclein degradation to decipher potential mechanisms underlying its role in disease. Chaperone mediated autophagy (CMA), a selective route of direct lysosomal degradation, participates in the turnover of α-synuclein. In a mouse model of synucleinopathy, we show that the levels of the CMA receptor Lamp-2a are dynamically upregulated upon the development of motor symptoms in the regions that form the most prominent inclusions. However, increased levels of Lamp-2a were unable to induce greater lysosomal substrate binding and degradation. The regions of the brain that develop the most prominent inclusions were found to have decreased CMA activity compared to the regions of the brain that develop minimal inclusions. Additionally, markers of lysosome and autophagosome levels were decreased in the inclusion-forming regions. Therefore, multiple lysosomal deficiencies potentially contribute to the selective aggregation of α-synuclein. However, during such conditions of impaired degradation, many substrates are presumably affected. Therefore, we next investigated potential factors that mediate the vulnerability of α-synuclein to aggregation. While no defects were detected in the ability of α-synuclein to be recognized as a CMA substrate or unfolded for lysosomal uptake, altered levels of proteins involved in lipid metabolism were found in the regions vulnerable to inclusion formation. Finally, given the lack of correlation between Lamp-2a levels and CMA activity across brain regions, we explored the possibility that additional proteins may participate in the direct lysosomal uptake and degradation of substrates. These data provide evidence of regional insufficiencies in lysosomal function that underlie the selective initiation of α-synuclein aggregation.