Hypothyroidism induces motor deficit via altered cerebellar HB-EGF/EGFR and autophagy

in Journal of Endocrinology
Authors:
Jitendra Vishwakarma Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow-226001, Uttar Pradesh, India
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India

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Keerti Gupta Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow-226001, Uttar Pradesh, India
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India

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Juhi Mishra Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow-226001, Uttar Pradesh, India

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Asmita Garg Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow-226001, Uttar Pradesh, India
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India

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Rafat Malik Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow-226001, Uttar Pradesh, India

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Amit Kashyap Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow-226001, Uttar Pradesh, India

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Manoj Shukla Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow-226014, Uttar Pradesh, India

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Dhirendra Singh Central Pathology Laboratory, Regulatory Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR–IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow-226001, Uttar Pradesh, India

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Sanghamitra Bandyopadhyay Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow-226001, Uttar Pradesh, India
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India

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https://orcid.org/0000-0003-0141-7388

Correspondence should be addressed to S Bandyopadhyay: sanghmitra@iitr.res.in

†(J Mishra is now at Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA)

††(R Malik is now at Department of Neuropathology, Neuroscience Centre, All India Institute of Medical Sciences, New Delhi, India)

DOI:
https://doi.org/10.1530/JOE-22-0338
Volume/Issue:
Volume 257: Issue 1
Article Type:
Research Article
Article ID:
e220338
Online Publication Date:
14 Mar 2023
Copyright:
© Society for Endocrinology 2023
Restricted access
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Thyroid hormones (TH) are vital for brain functions, while TH deficiency, i.e. hypothyroidism, induces neurological impairment in children and adults. Cerebellar neuronal apoptosis and motor deficits are crucial events in hypothyroidism; however, the underlying mechanism is less-known. Using a methimazole-treated hypothyroidism rat model, we investigated cerebellar autophagy, growth factor, and apoptotic mechanisms that participate in motor functions. We first identified that methimazole up-regulated cerebellar autophagy, marked by enhanced LC3B-II, Beclin-1, ATG7, ATG5-12, p-AMPKα/AMPKα, and p62 degradation as well as reduced p-AKT/AKT, p-mTOR/mTOR, and p-ULK1/ULK1 in developing and young adult rats. We probed upstream effectors of this abnormal autophagy and detected a methimazole-induced reduction in cerebellar phospho-epidermal growth factor receptor (p-EGFR)/EGFR and heparin-binding EGF-like growth factor (HB-EGF). Here, while a thyroxine-induced TH replenishment alleviated autophagy process and restored HB-EGF/EGFR, HB-EGF treatment regulated AKT-mTOR and autophagy signaling in the cerebellum. Moreover, neurons of the rat cerebellum demonstrated this reduced HB-EGF-dependent increased autophagy in hypothyroidism. We further checked whether the above events were related to cerebellar neuronal apoptosis and motor functions. We detected that comparable to thyroxine, treatment with HB-EGF or autophagy inhibitor, 3-MA, reduced methimazole-induced decrease in Nissl staining and increase in c-Caspase-3 and TUNEL-+ve apoptotic count of cerebellar neurons. Additionally, 3-MA, HB-EGF, and thyroxine attenuated the methimazole-induced diminution in riding time on rota-rod and grip strength for the motor performance of rats. Overall, our study enlightens HB-EGF/EGFR-dependent autophagy mechanism as a key to cerebellar neuronal loss and functional impairments in developmental hypothyroidism, which may be inhibited by HB-EGF and 3-MA treatments, like thyroxine.

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Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© Society for Endocrinology 2023
Article ID:
e220338
Article Type:
Research Article
Received Date:
23 Dec 2022
Accepted Date:
19 Jan 2023
Print Publication Date:
01 Apr 2023
Online Publication Date:
14 Mar 2023
Keywords:
TH deficiency; cerebellum; autophagy; growth factor; apoptosis; motor function

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