Butcher NJ, Kiehl TR, Hazrati LN, Chow EW, Rogaeva E, Lang AE, Bassett AS. Association Between Early-Onset Parkinson Disease and 22q11.2 Deletion Syndrome: Identification of a Novel Genetic Form of Parkinson Disease and Its Clinical Implications. JAMA Neurol. 2013 Nov 1;70(11):1359-66. PubMed.
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National Institute on Aging
The authors provide convincing evidence that links chromosome 22q11 deletions to PD. Although patients with 22q11 and LRRK2 mutations share many neuropathological abnormalities, it remains to be determined whether they follow similar pathogenic pathways. For example, disease onset is much earlier in the 22q11 cases, and the clinical syndrome is perhaps more severe, too.
One interesting aspect of 22q11 deletion is the potential impairment of microRNA processing mediated by DGCR8. LRRK2 is shown to regulate microRNA function, too (Gehrke et al., 2010). But we don't know whether DGCR8 and LRRK2 affect a similar subset of microRNAs critical for the function and survival of dopaminergic neurons.
Based on the algorithm we used, LRRK2 is not a good target for miR-185; however, that needs to be tested experimentally. If miR-185 indeed controls the expression of LRRK2 protein, the alteration of LRRK2 expression may contribute to the pathogenesis of 22q11 deletion. But LRRK2, at best, is just one of the downstream targets for miR-185 or DGCR8. The 22q11 mutation is going to be helpful in understanding the pathogenic mechanism of PD more broadly.
With the availability of various 22q11-related mouse models generated for the previous schizophrenia studies, it would be interesting to interrogate these mice to identify the critical genes involved in the PD-related phenotypes.
References:
Gehrke S, Imai Y, Sokol N, Lu B. Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression. Nature. 2010 Jul 29;466(7306):637-41. PubMed.
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