Case Suggests Toxic Clumps of TDP-43 Protein as Cause of Parkinson’s

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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The accumulation of toxic clumps of the protein TDP-43 — rather than alpha-synuclein protein, considered the hallmark of Parkinson’s disease — likely was the cause of death of nerve cells in a 60-year-old Japanese man diagnosed with the neurodegenerative disease, a case report shows.

The findings suggest the need to consider TDP-43 protein buildup, commonly found in people with amyotrophic lateral sclerosis (ALS), as a potential cause of Parkinson’s, according to researchers.

The study, “TDP-43 Proteinopathy Presenting with Typical Symptoms of Parkinson’s Disease,” was published in the journal Movement Disorders.

Parkinson’s disease typically is characterized by the accumulation of toxic clumps of misfolded alpha-synuclein protein, known as Lewy bodies. Their buildup within dopamine-producing nerve cells — those responsible for releasing the neurotransmitter dopamine — results in the cells’ death.

Dopamine is a chemical messenger that allows nerve cells to communicate and, among other functions, helps regulate movement. The loss of dopamine-producing nerve cells in certain regions of the brain is believed to give rise to Parkinson’s symptoms. Thus, the accumulation of alpha-synuclein is considered one of the causes of Parkinson’s disease.

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Now, researchers at the Osaka University Graduate School of Medicine, in Japan, described the case of a 60-year-old Japanese man diagnosed with Parkinson’s, in whom nerve cell death was not related to alpha-synuclein buildup.

No alpha-synuclein clumps found in brain

The man, which had no family history or gene mutations predisposing him to Parkinson’s, was diagnosed with the disease after showing gait impairments. Clinical examination revealed typical symptoms, including rigidity, slow movement, and balance problems. A CT brain scan showed a decrease in dopamine signaling in the striatum, a brain region involved in voluntary movement control.

He received treatment with levodopa, or L-DOPA — a precursor to dopamine — and responded well. Twelve years after his diagnosis, the man died of respiratory failure due to pneumonia.

His body was autopsied and his brain examined closely. The results revealed a marked loss of nerve cells and heightened inflammation in the substantia nigra, a brain region involved in the control of voluntary movements — and one of the most affected in Parkinson’s disease. However, there was no evidence of Lewy bodies containing alpha-synuclein in any of the regions normally affected in Parkinson’s.

“This was unusual,” Rika Yamashita, MD, of the school’s department of neurology, and the report’s first author, said in a press release.

Further analysis, however, showed clumps of another protein, called TDP-43. Aggregates of TDP-43 protein are commonly found in people with other neurodegenerative diseases, namely ALS and frontotemporal lobar degeneration, but are not usually associated with Parkinson’s.

These new findings suggest that toxic clumps of TDP-43 may lead to cell death in the substantia nigra and trigger the typical motor symptoms of Parkinson’s disease.

“This report has implications for how we think about the development of PD [Parkinson’s disease],” said Goichi Beck, MD, PhD, also from Osaka’s neurology department, and the report’s corresponding author.

“Much of the current research looking for [Parkinson’s] treatments is very focused on alpha-synuclein—but it may not be the only protein that causes the disease. Our findings indicate that TDP-43 accumulation may be a cause of [Parkinson’s disease] separate from alpha-synuclein accumulation,” Beck said.

According to the press release, these findings support the need for future studies to consider TDP-43 as a potential trigger for cell death in Parkinson’s and as a potential therapeutic target.

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