Human Alpha-synuclein Transgenic Mice: A Novel Animal Model of Lower Urinary Tract Dysfunction in Parkinson’s disease
Richard T. Kershen, M.D., Margaret Vizzard, PhD, Robert Hamill, M.D..
University of Vermont, Burlington, VT, USA.
Lower urinary tract dysfunction (LUTD) is common in patients with Parkinson’s disease (PD) and results in significant morbidity. Though the clinical manifestations and urodynamic spectrum of LUTD in PD have been well described, pathophysiologic mechanisms are poorly elucidated. An animal model for LUTD in PD would have enormous utility in this regard. Recently, transgenic (Tg) mice which constitutively over-express, human alpha-synuclein (Hα-SN; a peptide found in the Lewy body, the histopathologic hallmark of PD) have been developed. These mice exhibit neuro-pathologic changes and motor symptoms typical of human PD. Whether they develop LUTD similar to human PD patients has not been investigated. We aimed to characterize voiding function in Hα-SN Tg mice and investigate bladder expression of nerve growth factor (NGF) to examine its potential role in LUTD in PD.
Mice hemizygous (HZ) for Hα-SN were obtained from a commercial supplier. A hemizygous (HZ) breeding scheme was employed. Genotyping identified homozygous (HO), HZ and wildtype (wt) littermates. Monthly motor testing to identify the onset of clinical PD was performed on all genotypes beginning at five months of age. Monthly conscious cystometery was performed in HO and wt mice beginning at five months of age and continued through fifteen months of age (n=4-8 at each age). The urinary bladders of eight month old HO (n=3) and wt mice (n = 3) were analyzed for expression of NGF utilizing immunohistochemistry and enzyme linked immunoassays (ELISAs).
Motor dysfunction typical of the Hα-SN Tg mouse phenotype (clinical PD) was observed in HO mice only, beginning at twelve months of age. Similarly, only HO mice exhibited LUTD on conscious cystometry (onset at five months). A variety of urodynamic LUTD’s were revealed: detrusor overactivity (DO) with increased voiding (terminal DO (most common (67% of animals)) and non-voiding bladder contractions, urinary incontinence suggestive of impaired urethral closure and detrusor underactivity with decreased voiding frequency and increased bladder capacity. There was no association between mouse age and any type of dysfunction. HO mice exhibiting terminal DO demonstrated decreased cystometric bladder capacity (p ≤ 0.01), increased non-voiding bladder contractions (p ≤ 0.01) and elevated residual volumes (p ≤ 0.01). HO mice had increased bladder expression of NGF by immunohistochemisry and significantly increased NGF protein content per ELISAs (p ≤ 0.05).
We have demonstrated that mice homozygous for Hα-SN have LUTD similar to humans with PD. Of interest, LUTD in these animals appears to precede observable motor dysfunction by up to seven months. DO appears to be the most commonly observed urodynamic finding and is associated with reduced capacity and elevated post-void residuals. These findings mimic the storage and voiding abnormalities observed in human PD. NGF appears to be overexpressed in the bladders of HO mice suggesting that LUTD in these animals may be associated with alterations in bladder innervation presumably induced by autonomic nervous system disturbances. We believe that this novel animal model will provide a platform for future studies directed at unravelling the pathophysiologic mechanisms underlying LUTD in PD.