In @entity179 , it remains unclear why certain brain regions are selectively vulnerable to @entity6960 . In @entity19 expressing @entity1 @entity20098 a-synuclein, the brainstem and spinal cord develop the most prominent a-synuclein inclusions which correlate with age-dependent @entity66 . 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 a-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 @entity9674 . Using antibodies, brain tissue from @entity9674 null @entity19 , enzymatic deglycosylation, and mass spectrometry, we identified @entity9674 as a novel 72kDa glycoprotein in the @entity19 brain. Examination of @entity9674 levels revealed differences in expression across brain regions. The brainstem and the spinal cord had a more than three-fold greater levels of @entity9674 as compared to regions less vulnerable to aggregation and exhibited a selective upregulation of @entity9674 during development of a-synuclein inclusions. Despite this dynamic response of @entity9674 , 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 @entity9674 . These regional differences in CMA activity and @entity9674 expression were found in both non- @entity19 as well as @entity20098 a-syn @entity19 . Therefore, these are inherent variations and not a transgene-specific effect. However, differences in CMA activity may render select brain regions vulnerable to @entity409 in the presence of stressors such as overexpression of @entity1 @entity20098 a-syn. Collectively, the data provide a potential mechanism to explain the dichotomy of vulnerability or resistance that underlies brain regions during aggregate formation in @entity179 .

Regional deficiencies in chaperone-mediated autophagy underlie a-synuclein aggregation and XXXX .

@entity1 :: ('9606', 'Species') :: ['human'] @entity66 :: ('MESH:D004194', 'Disease') :: ['motor dysfunction'] @entity19 :: ('10090', 'Species') :: ['mice', 'mouse', 'transgenic mice'] @entity409 :: ('MESH:D008107', 'Disease') :: ['homeostatic dysfunction'] @entity9674 :: ('16784(Tax:10090)', 'Gene') :: ['Lamp2a', 'Lamp-2a'] @entity179 :: ('MESH:D019636', 'Disease') :: ['neurodegenerative disease', 'neurodegenerative diseases'] @entity6960 :: ('MESH:D001796', 'Disease') :: ['protein aggregation'] @entity20098 :: ('c|SUB|A|53|T', 'DNAMutation') :: ['A53T']
@entity179 :: (MESH:D019636,Disease) :: ['neurodegeneration']
