In the June 6 Nature Genetics, scientists identify a new gene responsible for some cases of familial Parkinson’s disease (PD). Researchers led by Teepu Siddique and first author Han-Xiang Deng, Northwestern University Feinberg School of Medicine, Chicago, found loss-of-function mutations in TMEM230 in affected members of several families. They report that the transmembrane protein encoded by the gene sits on vesicles that recycle synaptic components in neurons. The finding adds weight to the hypothesis that the endosomal recycling system goes awry in Parkinson’s disease (PD).

“This is a pretty comprehensive analysis,” said Mark Cookson, National Institute on Aging, Bethesda, Maryland. “The cell biology is very consistent with other genes linked to PD, particularly SNCA and LRRK2. It fits with what we might expect to see,” he said. While Cookson considered the data strong, he stressed the need for independent replication. 

The discovery started with a large North American family in Saskatchewan, Canada. Fifteen members from three generations developed PD between the ages of 48 and 85 in an autosomal-dominant fashion, but none carried mutations in known PD genes, such as SNCA, LRRK2, or VPS35. Scientists had been studying this family for 20 years, but were unable to pinpoint which gene caused their disease. In an independent study, researchers led by Matthew Farrer, University of British Columbia, Vancouver, had found a variant in the gene for DNAJC13 that partially segregated with disease, but three affected members did not carry the variant, while one without symptoms did (Vilariño-Güell et al., 2013). DNAJC13 encodes a protein that regulates clathrin coats on early endosomes. 

Now, Deng and colleagues report a different mutation runs in this same kindred. The scientists found that all affected family members shared the same genetic sequence on the tip of the short arm of chromosome 20. Guessing that the disease-causing variant was hiding somewhere in this neighborhood of 141 genes, the researchers used whole-exome sequencing to look for codon changes. A search of more than 800 additional PD patients from North America turned up two other mutations in this gene, both associated with early onset disease. One added six amino acids to the TMEM230 C-terminal tail and was found in a man who had been diagnosed at age 33. The second replaced a tyrosine with a cysteine at amino acid 92 and was found in a man who developed PD at age 34. These two variants, and the original R141L, were absent from more than 1,000 controls from North America. 

Looking farther afield, Deng searched for mutations in a Chinese Parkinson’s cohort comprising 225 familial and 349 sporadic cases. He found another TMEM230 mutation in nine patients from seven unrelated families. Five were homozygous for the mutation, indicating that both parents carried at least one copy of the variant. Since one of the parents remained free of any symptoms at 96 years old, the authors suggested this particular mutation may not be fully penetrant.

This mutation, which did not turn up in Chinese controls, adds seven amino acids to the C-terminal tail of TMEM230. Curiously, this addition, and the six-amino-acid addition found in the North American cohort, have the same last five amino acids.

The scientists wondered what TMEM230 does in the cell. Computer models predicted it to be a transmembrane protein, but it was biochemically uncharacterized. All four mutations appeared in areas expected to lie outside or inside the plasma membrane (see image below). 

Protein Structure.

TMEM230 sits in the plasma membrane by virtue of its two α-helical regions (blue). All four mutations linked to PD (red and blue circles) lie outside those areas. [Courtesy of Deng et al., Nature Genetics.]

Immunohistochemical staining in mouse brain sections revealed that TMEM230 sat on neuronal vesicles. Examining mouse neuroblastoma cells via confocal microscopy, the researchers found these vesicles throughout the cytoplasm, clustering especially around the nucleus. They tested positive for markers of the trans-Golgi network, synaptic vesicles, and early and recycling endosomes, but not for markers of lysosomes, mitochondria, or endoplasmic reticulum. TMEM230 also co-localized with VPS35, a component of the retromer complex, which helps recycle receptors from endosomes to the trans-Golgi network. This hinted that TMEM230 sits on the endosomes that recycle synaptic material for the cell.

What do the TMEM230 mutations do? The scientists expressed each one in primary mouse neurons and found by live imaging that synaptic vesicles moved more slowly in all of them than in controls. This implies that these are loss-of-function mutations that slow cellular recycling, allowing proteins such as α-synuclein to build up in the cell and aggregate, the authors suggested. In human embryonic kidney cells, the mutant proteins increased levels of α-synuclein. “The therapeutic implication is that if you are trying to develop drugs, you would not want to inhibit [TMEM230] function,” said Cookson. TMEM230 also turned up in Lewy bodies in midbrain and neocortex sections from 10 patients who had sporadic Parkinson’s and seven more who had dementia with Lewy bodies.

The data fits with other evidence that deficits in endosomal recycling are characteristic of PD, the authors wrote. Mutations in LRRK2 and VPS35 have been tied to familial PD, and both appear to function in endosomal pathways (Steger et al., 2016Jul 2011 news). “This study gives us a new variant, previously unknown, that can be exploited and leveraged for understanding Parkinson’s pathogenesis,” Siddique told Alzforum. Changing the regulation of TMEM230, or otherwise changing vesicular transport, may change the dynamics of disease, he said.

This genetics paper stands out by including a fair amount of cell biology, said Scott Small, Columbia University, New York. That many familial PD genes seem to converge on a similar biological pathway lends support to the idea that endosomal trafficking is relevant to neurodegeneration. “The link between endosomal trafficking and Parkinson’s disease is an emerging idea,” he told Alzforum. “That’s important for neurons because recycling of neurotransmitters and various membrane-bound receptors is critical for their function.”

Farrer agreed that TMEM230 may harbor disease-causing mutations in the Saskatchewan family. However, he cautioned that in the most recent generation Deng and colleagues reported, 11 mutation carriers remained free of symptoms. Their ages were not listed, perhaps to ensure privacy, but Farrer predicts many are in the range of disease onset. Siddique said that since there is such a wide range of onset age in this family, it is not surprising that some carriers have not yet developed disease. Farrer also noted that since it is often difficult to collect multigenerational genetic information, evidence that TMEM230 mutations cause diseased in all the Chinese family members is limited. Nevertheless, he called the finding interesting, and said it suggests synaptic-endosomal biology is important for familial PD. Perhaps both DNAJC13 and TMEM230 contribute to disease, and this would deserve more attention, he said.—Gwyneth Dickey Zakaib


  1. We have assessed the evidence for TMEM230 mutations as a cause of Parkinson's disease, and question the validity of the original work by Deng and colleagues, 2016. We conclude 'TMEM230 is NOT a gene for Parkinson's disease' (see bioRχiv for details).

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News Citations

  1. Sorting Out Parkinson’s: Exome Sequencing Points to Recycling Defect

Paper Citations

  1. . DNAJC13 mutations in Parkinson disease. Hum Mol Genet. 2014 Apr 1;23(7):1794-801. Epub 2013 Nov 11 PubMed.
  2. . Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases. Elife. 2016 Jan 29;5 PubMed.

Further Reading


  1. . Genes associated with Parkinson's disease: regulation of autophagy and beyond. J Neurochem. 2015 Jul 30; PubMed.

Primary Papers

  1. . Identification of TMEM230 mutations in familial Parkinson's disease. Nat Genet. 2016 Jul;48(7):733-9. Epub 2016 Jun 6 PubMed.