In neurodegenerative diseases, it remains unclear why certain brain regions are 
selectively vulnerable to protein aggregation. In transgenic mice expressing 
human A53T α-synuclein, the brainstem and spinal cord develop the most prominent 
α-synuclein inclusions which correlate with age-dependent motor dysfunction. 
Herein we present the novel finding that this selective aggregation is in part 
dependent on the inability of chaperone-mediated autophagy (CMA) to effectively 
degrade α-synuclein in these brain regions. Lysosomal assays revealed that CMA 
activity was significantly decreased in aggregation-prone regions compared to 
the remainder of the brain. Previously, CMA activity has been shown to be 
proportional to levels of the CMA receptor Lamp-2a. Using antibodies, brain 
tissue from Lamp-2a null mice, enzymatic deglycosylation, and mass spectrometry, 
we identified Lamp2a as a novel 72kDa glycoprotein in the mouse brain. 
Examination of Lamp-2a levels revealed differences in expression across brain 
regions. The brainstem and the spinal cord had a more than three-fold greater 
levels of Lamp-2a as compared to regions less vulnerable to aggregation and 
exhibited a selective upregulation of Lamp-2a during development of α-synuclein 
inclusions. Despite this dynamic response of Lamp-2a, the levels of substrates 
bound to the brain lysosomes as well as the rates of substrate uptake and 
degradation were not proportional to the levels of Lamp-2a. These regional 
differences in CMA activity and Lamp-2a expression were found in both 
non-transgenic mice as well as A53T α-syn mice. Therefore, these are inherent 
variations and not a transgene-specific effect. However, differences in CMA 
activity may render select brain regions vulnerable to homeostatic dysfunction 
in the presence of stressors such as overexpression of human A53T α-syn. 
Collectively, the data provide a potential mechanism to explain the dichotomy of 
vulnerability or resistance that underlies brain regions during aggregate 
formation in neurodegenerative disease.