Expression of tyrosine hydroxylase isoforms and phosphorylation at serine 40 in the human nigrostriatal system in Parkinson's disease

Jacqueline Shehadeh; Kay L Double; Karen E Murphy; Larisa Bobrovskaya; Stefanie Reyes; Peter R Dunkley; Glenda M Halliday; Phillip W Dickson

doi:10.1016/j.nbd.2019.104524

Expression of tyrosine hydroxylase isoforms and phosphorylation at serine 40 in the human nigrostriatal system in Parkinson's disease

Neurobiol Dis. 2019 Oct:130:104524. doi: 10.1016/j.nbd.2019.104524. Epub 2019 Jul 2.

Authors

Jacqueline Shehadeh¹, Kay L Double², Karen E Murphy³, Larisa Bobrovskaya⁴, Stefanie Reyes², Peter R Dunkley¹, Glenda M Halliday⁵, Phillip W Dickson⁶

Affiliations

¹ School of Biomedical Sciences and Pharmacy and Hunter Medical Research Institute, The University of Newcastle, Callaghan, NSW, Australia.
² Brain and Mind Centre, Discipline of Pharmacology, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.
³ Neuroscience Research Australia, Randwick, Australia.
⁴ School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, SA, Australia.
⁵ Neuroscience Research Australia, Randwick, Australia; Brain and Mind Centre, Central Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; School of Medical Sciences, University of New South Wales, Kensington, NSW, Australia.
⁶ School of Biomedical Sciences and Pharmacy and Hunter Medical Research Institute, The University of Newcastle, Callaghan, NSW, Australia. Electronic address: phil.dickson@newcastle.edu.au.

PMID: 31276794
DOI: 10.1016/j.nbd.2019.104524

Abstract

Tyrosine hydroxylase is the key enzyme controlling the synthesis of the catecholamines including dopamine. The breakdown of dopamine into toxic compounds has been suggested to have a key role in the degeneration of the dopaminergic neurons in Parkinson's disease. Humans are unique in containing four isoforms of tyrosine hydroxylase, but understanding of the role of these isoforms under normal conditions and in disease states is limited. The aim of this work was to determine the level and distribution of the four human isoforms in tissues from healthy controls and patients with Parkinson's disease. The results show that isoform 1 and isoform 2 are the major tyrosine hydroxylase isoforms in human brain, but that tyrosine hydroxylase isoform 2 is more abundant in the substantia nigra than the tyrosine hydroxylase isoform 1. The two minor isoforms, isoform 3 and isoform 4, are expressed at a proportionally higher level in the terminal field regions (caudate and putamen) compared to the substantia nigra. There was a selective loss of tyrosine hydroxylase isoform 1 in Parkinson's disease compared to age-matched controls and a corresponding increase in the proportion of tyrosine hydroxylase isoform 2. Phosphorylation of serine 40 was significantly increased in caudate, putamen and ventral tegmental area, but not in the substantia nigra, in Parkinson's disease brain. These results show a selective sparing of tyrosine hydroxylase isoform 2 in Parkinson's disease. Isoform 2 exhibits a reduced capacity for activation compared to isoform 1, which may account for the selective sparing of cells expressing isoform 2 in Parkinson's disease. Surviving neurons in Parkinson's disease brain exhibit a substantial increase in tyrosine hydroxylase phosphorylation consistent with a compensatory mechanism of increased dopamine synthesis in the terminal field regions.

Keywords: Human; Isoform; Neurodegeneration; Parkinson's disease; Phosphorylation; Tyrosine hydroxylase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Corpus Striatum / metabolism*
Dopaminergic Neurons / metabolism
Humans
Parkinson Disease / metabolism*
Phosphorylation
Protein Isoforms / metabolism*
Substantia Nigra / metabolism*
Tyrosine 3-Monooxygenase / metabolism*

Substances

Protein Isoforms
Tyrosine 3-Monooxygenase