1: Ann Neurol. 2007 Aug;62(2):145-53.

Tau and alpha-synuclein in susceptibility to, and dementia in, Parkinson's
disease.

Goris A, Williams-Gray CH, Clark GR, Foltynie T, Lewis SJ, Brown J, Ban M,
Spillantini MG, Compston A, Burn DJ, Chinnery PF, Barker RA, Sawcer SJ.

Department of Clinical Neurosciences (Neurology Unit), University of Cambridge,
Cambridge, United Kingdom. an.goris@med.kuleuven.be

OBJECTIVE: Parkinson's disease (PD) is a neurodegenerative condition that
typically presents as a movement disorder but is known to be associated with
variable degrees of cognitive impairment including dementia. We investigated the
genetic basis of susceptibility to and cognitive heterogeneity of this disease.
METHODS: In 659 PD patients, 109 of which were followed up for 3.5 years from
diagnosis, and 2,176 control subjects, we studied candidate genes involved in
protein aggregation and inclusion body formation, the pathological hallmark of
parkinsonism: microtubule-associated protein tau (MAPT), glycogen synthase
kinase-3beta (GSK3B), and alpha-synuclein (SNCA). RESULTS: We observed that
cognitive decline and the development of PD dementia are strongly associated (p =
10(-4)) with the inversion polymorphism containing MAPT. We also found a novel
synergistic interaction between the MAPT inversion polymorphism and the single
nucleotide polymorphism rs356219 from the 3' region of SNCA. In our data,
carrying a risk genotype at either of these loci marginally increases the risk
for development of PD, whereas carrying the combination of risk genotypes at both
loci approximately doubles the risk for development of the disease (p = 3 x
10(-6)). INTERPRETATION: Our data support the hypothesis that tau and
alpha-synuclein are involved in shared or converging pathways in the pathogenesis
of PD, and suggest that the tau inversion influences the development of cognitive
impairment and dementia in patients with idiopathic PD. These findings have
potentially important implications for understanding the interface between tau
and alpha-synuclein pathways in neurodegenerative disorders and for unraveling
the biological basis for cognitive impairment and dementia in PD.


PMID: 17683088 [PubMed - indexed for MEDLINE]