RAB32, a new Parkinson's gene

Happy Sunday! A new gene, RAB32, has been linked with Parkinson's disease (PD) through exome sequencing of PD families. Two groups have independently identified the gene through analyses of independent cohorts of familial PD (Hop, Lai, et al. Nat Genet 2024; Gustavsson et al. Lancet Neurol 2024). Mind you, RAB32 is not just another gene that is getting linked to PD. It comes as an important piece in the puzzle researchers have been putting together for decades since LRRK2, a frequently mutated gene in PD, was discovered.

I've known about LRRK2 and that many companies are developing drugs to inhibit this gene in the brain to treat PD. But I never realized LRRK2 is a field of its own and hundreds of researchers across the world are religiously studying this one gene since 2004, trying to understand how LRRK2 mutations result in the death of dopaminergic neurons in the brain. It all started with two publications in 2004 in the journal Neuron.

One of the many loci mapped to PD through family-based linkage analysis was PARK8, a large locus spanning the centromere ends of short and long arms of chromosome 12, reported first in 2002. The linkage region spans many millions of base pairs and hold more than 100 genes. The locus was originally mapped in a Japanese family, but soon in families in the Europe, UK and US. The PD-causing gene was dragged out of the gene-dense forest in 2004 by two research groups, one led by Thomas Gasser from the University of Tübingen in Germany (Zimprich et al. Neuron 2004) and the other, Andrew Singleton from the NIH in the US (Paisán-Ruíz et al. Neuron 2004)

Thanks to a series of families from Basque region of Spain, the disease markers that segregated in these families helped Singleton and colleagues to narrow down the disease locus from ~12 Mbp containing 116 genes to ~2 Mbp containing 11 genes and eventually to the causative gene, LRRK2. The gene encodes a gigantic protein made of 2,482 amino acids. Honoring the Basque families that helped clone this gene, the authors named this gene as