Autosomal dominantly inherited Parkinson's disease: first investigation of the brain of a patient with the A30P mutation in the alpha-synuclein gene and initial insights into the degenerative process

Abstract

To date, three point mutations in the alpha-synuclein (SNCA) gene (Ala30Pro, Glu46Lys, and Ala53Thr) have been identified in families with autosomal dominantly inherited Parkinson's disease (PD). Carriers of the Ala30Pro mutation in the SNCA gene display typical clinical signs of idiopathic Parkinson's disease (IPD), including a positive and sustained response to levodopa therapy. The observation that SNCA represents the major component of the IPD-related inclusion bodies (Lewy neurites, Lewy bodies) raised the possibility that SNCA might contribute to neurodegeneration via protein misfolding and aggregation. Biochemical studies of the aggregate-forming capacity consistently showed reduced aggregation of Ala30Pro SNCA compared to Ala53Thr and Glu46Lys mutant protein in vitro. Thus, it has been speculated that Ala30Pro SNCA might involve different pathological alterations leading to neurodegeneration than the other two mutations. Since the relationship between familial PD caused by the A30P mutation and the more common IPD form is unclear and no brain tissue from an individual with this SNCA mutation has been examined to date, ours is the first pathoanatomical study of the brain of a patient with the A30P mutation in the SNCA gene. The results indicate the existence of: (1) brain abnormalities of similar type and distribution commonly seen in late IPD stages, that in part exceeded the severity and extent of these IPD-related abnormalities; (2) marked white matter loss in the frontal, temporal, and parietal lobes; (3) neuronal loss in the substantia nigra, locus coeruleus, lateral vestibular and dorsal motor vagal nuclei; (4) widespread occurrence of alpha-synuclein immunopositive Lewy bodies, Lewy neurites, fiber tracts and coiled bodies. Theses insights into the pathological process that underlies familial PD as caused by the A30P mutation may help to understand the relationship between this form of familial PD and the more frequently occurring IPD.