Body weight (BW) loss and reduced body mass index (BMI) are the most common peripheral alterations in Huntington disease (HD) and have been found in HD mutation carriers and HD animal models before the manifestation of neurological symptoms. This suggests that, at least in the early disease stage, these changes could be due to abnormal tissue growth rather than tissue atrophy. Moreover, BW and BMI are reported to be more affected in males than females in HD animal models and patients. Here, we confirmed sex-dependent growth alterations in the BACHD rat model for HD and investigated the associated contributing factors. Our results showed growth abnormalities along with decreased plasma testosterone and insulin-like growth factor 1 (IGF-1) levels only in males. Moreover, we demonstrated correlations between growth parameters, IGF-1, and testosterone. Our analyses further revealed an aberrant transcription of testosterone biosynthesis-related genes in the testes of BACHD rats with undisturbed luteinizing hormone (LH)/cAMP/PKA signaling, which plays a key role in regulating the transcription process of some of these genes. In line with the findings in BACHD rats, analyses in the R6/2 mouse model of HD showed similar results. Our findings support the view that mutant huntingtin may induce abnormal growth in males via the dysregulation of gene transcription in the testis, which in turn can affect testosterone biosynthesis.

No single animal model can recapitulate all the features of a particular human disease on its own. Historically, rats have been used to study neurobiology and underlying functional networks. Likewise, rat models have been created to study neurodegenerative mechanisms and therapeutic interventions. In the last decades, a shift towards the use of mice has been observed in many research fields, not least because of the comparatively easier genetic manipulation of mice. However, with the full sequence of the rat genome being available, advances in genetic manipulation of the rat, and advanced test regimens and biomarkers at hand, the rat presents itself once more as a valuable model organism for studying neurodegenerative disorders. This review provides an overview of currently available, well-characterized rat models of Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, as well as their advantages for studying neurodegenerative disorders and evaluating therapeutic interventions.

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