Parkinson’s disease: A Gordian knot

Understanding the problems and possibilities related to Parkinson’s disease.
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Parkinson’s, a progressive disease that becomes worse over time. More specifically, Parkinson’s disease (PD) is a long-held, neurological disorder of the central nervous system that leads to certain movement-related problems.

The pathogenic characteristics of this disease such as aggregation of α-synuclein and lewy body formation in the substantia nigra region of the brain results in loss of motor abilities.

What leads to Parkinson’s disease?

To understand the cause, we first need to understand the alteration in neural circuitry involved in motor regulation in the basal ganglia of the brain. The basal ganglia is the region that plans the movement much before the actual movement via direct or indirect pathway.

In the case of Parkinson’s disease, the direct pathway of motor circuitry in basal ganglia gets disturbed due to loss of dopaminergic neurons which ultimately leads to Hypokinesia. Also, there are several factors like genetic, environmental, mitochondrial dysfunctioning, dysregulation in proteostasis, neuro-inflammation, and endoplasmic reticulum (ER) stress that adds to the problem.

A few recent studies strengthen the correlation of oxidative stress, ER stress, mitochondrial dysfunction, and HERPUD1 gene in ER-associated protein degradation.

What is HERP?

HERP (Homocysteine-inducible, endoplasmic reticulum protein), is a membrane-bound protein located in the ER regulating the ER-associated degradation (ERAD) process in several cells present in the brain tissues. HERP expression is strongly upregulated upon ER stress induction as observed in a study viral infection (EV-71 virus) based ER stress induction. This stress-based study can be replicated using other viruses like the Influenza virus, HTLV-1, and Sendai virus. ER stress induction leads to stimulation of MAVS (Mitochondrial anti-viral signaling protein) pathway, which further activates IRF and downstream signaling to increase the expression of IFNs and ISGs. HERP binds with TANK binding kinase-1 (TBK-1) to upregulate MAVS signaling.

The significance of HERP in finding possible cures for PD.

It has been found that upregulation of HERP protein is associated with protein aggregation and neuroinflammation in Parkinson’s disease. Another study demonstrates the association of HERP with Parkinson’s disease in the MPTP model of mice.

We are trying to target this potential candidate gene to prevent oxidative stress and ER stress with the help of exosomal tRF based downregulation. We believe that downregulation of these ER based genes will help in improving the PD-associated condition.

We hope to improve the PD condition and target several other factors that are worsening neurodegenerative based condition.

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