Autosomal dominant Lewy body dementia

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α-synuclein is a synaptic protein found in aggregates (Lewy bodies) in Parkinson's disease and dementia with Lewy bodies. It is also found as inclusions in the neuroglial in multiple system atrophy and in other abnormal disposition in several other neurodegenerative diseases of the central nervous system. It has recently been postulated that presynaptic alpha-synuclein aggregates may actually be the common association[1]. Further it seems a functional gut biome (bacterial colonisation) may be necessary to induce the neuropathology[2]. Accumulation of alpha-synuclein in cultured human dopaminergic neurons exposed to dopamine and oxygen radicals results in apoptosis. Alpha-synuclein is not toxic in nondopaminergic human cortical neurons.[3] An 11 amino acid core (NACore) appears to be responsible for the abnormal toxic amyloid deposition and these deposits can be too small to be seen on optical microscopy[4].

Mutations of alpha-synuclein gene (SNCA) at 4q21 cause some familial Parkinson's disease:

  • PARK1 (OMIM:168601) - various point mutations eg ala53-to-thr (A53T), ala30-to-pro (A30P) substitution and SNCA duplication.
  • PARK4 (OMIM:605543) - triplication
  • Autosomal dominant Lewy body dementia (OMIM:127750)- glu46-to-lys (E46K) mutation