Nuevos factores de riesgo genéticos para la enfermedad de Parkinson

A larga lista de variantes genéticas que reportábamos días atrás, y la aun mas larga lista en exploración, debemos agregar la confirmación de estas dos variantes que actúan como significativos factores de riesgo de EP multifactorial, es decir, aquellas formas que, en general, aparecen esporádicamente y con un inicio tardío (que constituyen la mayoría de los casos de EP).

Así como en los últimos anos se han delineado bien las formas de EP causadas por genes de efecto mayor (monogénicas o cuasi-monogénicas) parece irse conformando un “perfil genómico de riesgo” de EP, de forma similar a como se ha ido conformando para otras afecciones (fundamentalmente la enfermedad cardiovascular arteriosclerótica).


J Neural Transm. 2008 Aug;115(8):1141-8. Epub 2008 Apr 30.
A comprehensive genetic study of the proteasomal subunit S6 ATPase in German Parkinson's disease patients.
Wahl C, Kautzmann S, Krebiehl G, Strauss K, Woitalla D, Müller T, Bauer P, Riess O, Krüger R.
Laboratory of Functional Neurogenomics, Center of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tubingen, Germany.
Dysfunction of proteasomal protein degradation is involved in neurodegeneration in Parkinson's disease (PD). Recently we identified the regulatory proteasomal subunit S6 ATPase as a novel interactor of synphilin-1, which is a substrate of the ubiquitin-ligase Parkin (PARK2) and an interacting protein of alpha-synuclein (PARK1). To further investigate a potential role in the pathogenesis of PD, we performed a detailed mutation analysis of the S6 ATPase gene in a large sample of 486 German sporadic and familial PD patients. Direct sequencing revealed two novel intronic variants. An insertion/deletion variant in intron 5 of the S6 ATPase gene was more frequent in patients compared to controls. Moreover, this variant was significantly more frequent in early-onset compared to late-onset PD patients. The identification of a genetic link between a regulatory proteasomal subunit and PD further underscores the relevance of disturbed protein degradation in PD.


Hum Genet. 2008 Oct;124(3):287-8. Epub 2008 Sep 10.
LRRK2 R1628P increases risk of Parkinson's disease: replication evidence.
Tan EK, Tan LC, Lim HQ, Li R, Tang M, Yih Y, Pavanni R, Prakash KM, Fook-Chong S, Zhao Y.
Department of Neurology, Singapore General Hospital, National Neuroscience Institute, Outram Road, Singapore, 169608, Singapore. gnrtek@sgh.com.sg
We showed that the frequency of a LRRK2 variant (c.4883G > C, R1628P) was higher in Parkinson's disease (PD) compared to controls (8.4 vs. 3.4%, P = 0.046, OR 2.5, 95% CI 1.1-5.6). In the multivariate logistic regression (with adjustments made for the effect of age, age of onset, and gender), the heterozygous R1628P genotype was associated with an increased risk of PD compared to controls (OR 3.3, 95% CI 1.4- 7.9, P = 0.007). We provided an independent confirmation that the R1628P variant increases the risk of PD among Chinese.