ROCK2 inhibition: A futuristic approach for the management of Alzheimer's disease

Shalini Mani; Divya Jindal; Hitesh Chopra; Saurabh Kumar Jha; Sachin Kumar Singh; Gulam Md Ashraf; Mehnaz Kamal; Danish Iqbal; Dinesh Kumar Chellappan; Abhijit Dey; Saikat Dewanjee; Keshav K Singh; Shreesh Ojha; Inderbir Singh; Rupesh K Gautam; Niraj Kumar Jha

doi:10.1016/j.neubiorev.2022.104871

ROCK2 inhibition: A futuristic approach for the management of Alzheimer's disease

Neurosci Biobehav Rev. 2022 Nov:142:104871. doi: 10.1016/j.neubiorev.2022.104871. Epub 2022 Sep 16.

Authors

Shalini Mani¹, Divya Jindal², Hitesh Chopra³, Saurabh Kumar Jha⁴, Sachin Kumar Singh⁵, Gulam Md Ashraf⁶, Mehnaz Kamal⁷, Danish Iqbal⁸, Dinesh Kumar Chellappan⁹, Abhijit Dey¹⁰, Saikat Dewanjee¹¹, Keshav K Singh¹², Shreesh Ojha¹³, Inderbir Singh³, Rupesh K Gautam¹⁴, Niraj Kumar Jha¹⁵

Affiliations

¹ Centre for Emerging Disease, Department of Biotechnology, Jaypee Institute of Information Technology, Noida, UP, India. Electronic address: mani.shalini@gmail.com.
² Centre for Emerging Disease, Department of Biotechnology, Jaypee Institute of Information Technology, Noida, UP, India.
³ Chitkara College of Pharmacy, Chitkara University, Punjab, India.
⁴ Department of Biotechnology, School of Engineering and Technology (SET), Sharda University, Greater Noida, Uttar Pradesh 201310, India; Department of Biotechnology, School of Applied & Life Sciences (SALS), Uttaranchal University, Dehradun 248007, India; Department of Biotechnology Engineering and Food Technology, Chandigarh University, Mohali 140413, India.
⁵ School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411, Punjab, India.
⁶ Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, University City, Sharjah 27272, United Arab Emirates.
⁷ Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia.
⁸ Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah 11952, Saudi Arabia.
⁹ Department of Life Sciences, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.
¹⁰ Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata 700073, India.
¹¹ Advanced Pharmacognosy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India.
¹² Department of Genetics, UAB School of Medicine, The University of Alabama at Birmingham, United States.
¹³ Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, PO box 15551 Al Ain, Abu Dhabi, United Arab Emirates.
¹⁴ Department of Pharmacology, Indore Institute of Pharmacy, Indore, 453331, India. Electronic address: drrupeshgautam@gmail.com.
¹⁵ Department of Biotechnology, School of Engineering and Technology (SET), Sharda University, Greater Noida, Uttar Pradesh 201310, India; Department of Biotechnology, School of Applied & Life Sciences (SALS), Uttaranchal University, Dehradun 248007, India; Department of Biotechnology Engineering and Food Technology, Chandigarh University, Mohali 140413, India. Electronic address: niraj.jha@sharda.ac.in.

PMID: 36122738
DOI: 10.1016/j.neubiorev.2022.104871

Abstract

Neurons depend on mitochondrial functions for membrane excitability, neurotransmission, and plasticity. Mitochondrial dynamics are important for neural cell maintenance. To maintain mitochondrial homeostasis, lysosomes remove dysfunctional mitochondria through mitophagy. Mitophagy promotes mitochondrial turnover and prevents the accumulation of dysfunctional mitochondria. In many neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), mitophagy is disrupted in neurons. Mitophagy is regulated by several proteins; recently, Rho-associated coiled-coil containing protein kinase 2 (ROCK2) has been suggested to negatively regulate the Parkin-dependent mitophagy pathway. Thus, ROCK2 inhibition may be a promising therapy for NDDs. This review summarizes the mitophagy pathway, the role of ROCK2 in Parkin-dependent mitophagy regulation, and mitophagy impairment in the pathology of AD. We further discuss different ROCK inhibitors (synthetic drugs, natural compounds, and gene therapy-based approaches) and examine their effects on triggering neuronal growth and neuroprotection in AD and other NDDs. This comprehensive overview of the role of ROCK in mitophagy inhibition provides a possible explanation for the significance of ROCK inhibitors in the therapeutic management of AD and other NDDs.

Keywords: Alzheimer’s disease; Mitochondria; Mitophagy; Neurodegeneration; Neuroprotection; Parkin; ROCK.

Publication types

Review

MeSH terms

Alzheimer Disease* / metabolism
Humans
Mitochondria / metabolism
Mitophagy / genetics
Neurons / physiology
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism
rho-Associated Kinases / metabolism
rho-Associated Kinases / pharmacology

Substances

Ubiquitin-Protein Ligases
ROCK2 protein, human
rho-Associated Kinases