By Jay Nathan ’27

As researchers push towards pinpointing a cause for Parkinson’s disease, new genetic implications can
provide more insight into predicting diagnoses based on familial inheritance of the TMEM230 gene.
To fully understand these findings, we must first fully understand what Parkinson’s
disease really is. Parkinson’s disease (PD) is a neurodegenerative disorder affecting
1% of the population over 60. Its clinical features are a resting tremor, bradykinesia
(compromised mobility), rigidity, and postural instability. The pathological features of PD
are the loss of dopamine-producing neurons and the presence of Lewy bodies which
are clumps of protein particles that, for some still unknown reason, accumulate in the
brain. This accumulation leads to a loss of neural function, especially localized in the
substantia nigra which is a part of the brain that is instrumental in production and
signaling of dopamine.

Most cases of PD are sporadic with unknown cause, but rare familial cases can aid in
identifying genetic defects and model development. Several genes have been proven to
be linked to Parkinson’s disease, including SNCA and LRRK2. However, these
mutations tell us very little about the pathogenic mechanisms underpinning Parkinson’s
disease. That’s why the discovery of the TMEM230 in relation to PD is so important
since, according to Deng et al., TMEM could be the disease-causing gene.
The methods of isolation of this gene are as follows. The study’s subject was a large
North American family of northern European ancestry. There were 81 total members in
the family, with 15 affected by PD. There were variable symptoms of typical PD
observed in 14 affected individuals with disease onset mean age at 67.0 years with a
standard deviation of ± 9.5 years. For genetic analysis, researchers collected DNA
samples from 65 family members, including the 13 affected individuals and they
performed genome-wide linkage analysis. They saw significant LOD scores obtained for markers on chromosome 20p which helped them start to narrow down a location of the
disease causing gene. Throughout this process, they also took into account the genetic
haplotype that was shared by all 13 affected family members but not by unaffected
individuals in the second generation. This all helped in identifying the autosomal
dominant PD locus being in a minimum candidate region (MCR) of 10.7 Mb at 20pter-
p12 on chromosome 20.

Fig 1: Homozygosity mapping confirmed the PD locus to the short arm of chromosome
20.

Next, they did a series of tests to determine which specific gene was at play in PD.
There are 141 known genes in the 20pter-p12 MCR, so they needed to narrow down
their scope. They first tried gene analysis by Sanger sequencing, but they found no
variants. Next they tried whole-exome sequencing which worked wonderfully. Still, after
finding a total of 90289 variants, they still had to filter out a lot. By excluding variants
with heterozygosity >0.01, filtering for functional consequences (like nonsense,
missense, and splice-site mutations) and filtering out tolerated variants, they were able
to narrow down to a single variant. The TMEM230 variant was identified as a single
missense variant that mutated Arginine to Leucine. This mutation was present in 4
patients with PD (not the unaffected 1).

Fig 2: c.442G>T mutation, resulting in p.R141L. Wild-type sequence in upper panel,
heterozygous mutation in the lower panel.


Now, you may be wondering, what is the intended function of the TMEM gene? Well,
TMEM230 encodes a putative transmembrane protein of unknown function, so we don’t
really know exactly what it does, but it definitely encodes a protein for vesicles to
permeate through cell membranes, specifically at the synapse of a neuron. It is
hypothesized that there are two major α-helical domains and two transmembrane
segments in the protein and those are the most important domains of the protein. All
four mutations in the TMEM230 gene that we have touched upon, including the Arginine
to Leucine one, is mapped onto loop regions of the protein which are important for
binding two secondary structures together and a mutation could compromise the
protein’s ability to perform enzymatic functions, bind to ligands, etc.
Immunohistochemical staining of mouse brain sections showed TMEM230 localized to
vesicle structures in neurons, including dopaminergic neurons in the substantia nigra,
which as we have previously established, is highly associated with PD. Furthermore,
TMEM230 vesicle structures are predominantly located in the perinuclear region as
clusters and in cytosolic areas as isolated vesicles or vesicle clusters.
In conclusion, TMEM230 is suggested to control a functional pathway in synaptic
vesicle and endosome retrograde trafficking. The reason this may be causing PD
symptoms is because defects in synaptic vesicle and endosome trafficking may
correspond to a convergent pathway in Parkinson’s disease pathogenesis. The
therapeutic implications of these findings are vast and can help transform the way we
have been treating PD. For example, by aiming to modulate synaptic vesicle and
endosome trafficking in the brain, therapeutic effects may be much more successful.

Resources:
1) Deng et al. (2016). Identification of TMEM230 mutations in familial Parkinson’s
disease. Nature Genetics 48, 733-739.

Image Links:

  • Cover image Link: https://www.porterhousemedical.com/news/parkinsons-disease-a-hopeful-future/
  • Figure 1 Link: https://pubmed.ncbi.nlm.nih.gov/27270108/
  • Figure 2 Link: https://pubmed.ncbi.nlm.nih.gov/27270108/