Genetic and pathological links between Parkinson's disease and the lysosomal disorder Sanfilippo syndrome

Background: Parkinson's disease (PD) is a common neurodegenerative disorder of unknown etiology. The characteristic a-synuclein aggregation of PD is also a feature of Sanfilippo syndrome, a storage disorder caused by a-N-acetylglucosaminidase (NAGLU) gene mutations. We explored genetic links between these disorders and studied the pathology of Sanfilippo syndrome to investigate a common pathway toward a-synuclein aggregation. Methods: We typed the 2 single-nucleotide polymorphisms that tag the common haplotypes of NAGLU in 926 PD patients and 2308 controls and also stained cortical tissue from 2 cases of Sanfilippo A syndrome using the anti-a-synuclein antibody, Per7. Results: Allelic analysis showed an association between rs2071046 and risk for PD (P 1.3 x 10(-3)). Intracellular alpha-synuclein accumulation was observed in the cortical tissue of both Sanfilippo A syndrome cases. Conclusions: This study suggests a possible role of NAGLU in susceptibility to PD while extending evidence for a-synuclein aggregation in the brain in lysosomal storage disorders. Our findings support a mechanism involving lysosomal dysfunction more generally in the pathogenesis of PD. (C) 2011 Movement Disorder Society