Yvonne Davies

α-synuclein implicated in Parkinson’s disease catalyses the formation of hydrogen peroxide in vitro

Some rare inherited forms of Parkinsons disease (PD) are due to mutations in the gene encoding a 140-amino acid presynaptic protein called alpha-synuclein. In PD, and some other related disorders such as dementia with Lewy bodies, alpha-synuclein accumulates in the brain in the form of fibrillar aggregates, which are found inside the neuronal cytoplasmic inclusions known as Lewy bodies. By means of an electron spin resonance (ESR) spin trapping method, we show here that solutions of full-length alpha-synuclein, and a synthetic peptide fragment of alpha-synuclein corresponding to residues 61-95 (the so-called non-Abeta component or NAC), both liberate hydroxyl radicals upon incubation in vitro followed by the addition of Fe(II). We did not observe this property for the related beta- and gamma-synucleins, which are not found in Lewy bodies, and are not linked genetically to any neurodegenerative disorder. There is abundant evidence for the involvement of free radicals and oxidative stress in the pathogenesis of nigral damage in PD. Our new data suggest that the fundamental molecular mechanism underlying this pathological process could be the production of hydrogen peroxide by alpha-synuclein.

Pick's disease is associated with mutations in the tau gene

Recently, mutations within the tau gene have been associated with some familial forms of frontotemporal dementia. To investigate whether tau gene mutations are also associated with Picks disease, we analyzed the tau gene in 30 cases of pathologically confirmed Picks disease. Two coding mutations were identified in separate cases of Picks disease. A glycine‐to‐arginine mutation at codon 389 was detected in 1 case and a lysine‐to‐threonine mutation at codon 257 was identified in another. Analysis of dephosphorylated tau from the brain of the patient with the codon 389 mutation revealed a prominent band representing tau, with four microtubule‐binding domains and no amino terminal inserts. This is in contrast to Picks disease without any tau gene mutations, which consist of tau with mainly three microtubule‐binding domains and only a trace of tau, with four microtubule‐binding domains. Functional analysis of tau with these two mutations demonstrated a reduced ability of tau to promote microtubule assembly. Surprisingly, these mutations increased taus susceptibility to calpain I digestion, suggesting that this feature may be related to the formation of a Pick type of histology. Moreover, these data suggest that Picks disease is not a separate entity but part of the frontotemporal dementia disease spectrum. Ann Neurol 2000;48:859–867