A common thread in amyotrophic lateral sclerosis, Fronto-temporal dementia, Birt-Hogg-Dubé syndrome, vesicular trafficking and bacterial cell polarity

"I tired mid-season. I don't know why, but I just couldn't get going again" -Lou Gehrig (1938). One of the greatest American baseball first baseman was diagnosed with amyotrophic lateral sclerosis (ALS) in June 1939 and died two year later. 

Amyotrophic lateral sclerosis, or Lou Gehrig’s disease, is a debilitating motor neuron disease characterized by rapidly progressive muscular degenerations resulting in fatal paralysis. ALS is often known to occur in individuals with no family history. Studies on the inherited form, familial ALS, have shown that mutations in any of 19 genes can cause ALS, and analysis of the gene list does not reveal an obvious common thread. The neuropathological features include degeneration of corticospinal tracts and loss of lower motor neurons, and several distinct cell types in the primary motor cortex, and gliosis in the motor cortex and spinal cord. Like other neural diseases such as Parkinsonism or Alzheimer’s disease, the degenerating neurons show inclusion bodies of insoluble proteins, or proteins in complex with RNA. Several proteins have been reported in these inclusion bodies including ubiquitin, superoxide dismutase, peripherin, Dorfin, intermediate filament proteins and cystatin-C. Thus, although it has been a while since people recognized ALS, the many distinct causes and varying pathologies have posed great challenges with respect to diagnosis, treatment and understanding the mechanisms of the disease. It is in this regard that recent work from our group, while clarifying the origins of a particular type of ALS, adds new wrinkles to the story and opens up new doors for other poorly characterized proteins, some of which are implicated in human disease.

In 2011, two independent groups (DeJesus-Hernandez et al., Renton et al.) found that a mutation in the human gene C9orf72, is strongly associated with ALS and fronto-temporal dementia (FTD). This was the first gene that linked both these conditions. More precisely, the mutation involves an expansion of the hexanucleotide GGGGCC in the first intron of C9orf72. The absence of a protein defect led researchers to propose that the pathology of this disease may result from RNA-dominant toxicity or haploinsufficiency, supported by the presence of inclusion bodies with the RNA binding protein TDP-43. As of today, over 150 studies have been published regarding the role of C9orf72 mutations in ALS, and also many other neurodegenerative diseases such as Alzheimer's disease and mild cognitive impairment.

Using sensitive sequence and structure analyses, we unified the C9orf72 to a well-known family of GDP-GTP exchange factors (GEFs) for Rab GTPases known as the DENN module, divergent versions of which were also recently identified in Folliculin (Nookala et al.). Mutations in Folliculin cause the Birt-Hogg-Dubé syndrome. Additionally, we showed that the Folliculin interacting proteins FNIP1/2, the nitrogen permease regulators 2 and 3 (Npr2 and Npr3), and the SMCR8 protein encoded by a gene in the Smith-Magenis syndrome candidate region also contain DENN modules. Unification of these proteins to a module that partners with the Rab GTPases connects them to intracellular vesicular trafficking events. This opens a new angle for ALS pathology, i.e the possibility of a vesicular trafficking defect in individual with the C9orf72 mutation. Defects in vesicular trafficking proteins have been previously implicated in phenotypically comparable neurological diseases. For example, mutations in ALS2, which has been proposed to function as a GEF for Rab5, result in an infantile onset motor neuron disease similar to ALS from C9ORF72 mutations. Likewise, an adult onset atypical ALS ensues from mutations in VAPB (ALS8), which is a vesicular trafficking protein. A mutation in the dynactin gene responsible for distal hereditary motor neuronopathy type VIIB (HMN7B; distal spinal and bulbar muscular atrophy or dSBMA), might also result from defects in vesicular trafficking on microtubule tracks by the dynein motor (Laird et al.). Impairment of intracellular trafficking is also a commonly observed theme in several neural diseases such as Huntington’s, Parkinson’s, Niemann-Pick Type C, and Alzheimer’s disease.

The DENN module..... to be continued.

For now you can read our paper (Zhang et. al) and also a news story related to our work.