Antagonistic pleiotropy in mice carrying a CAG repeat expansion in the range causing Huntington’s disease

Abstract

Antagonist pleiotropy, where a gene exerts a beneficial effect at early stages and a deleterious effect later on in an animal’s life, may explain the evolutionary persistence of devastating genetic diseases such as Huntington’s disease (HD). To date, however, there is little direct experimental evidence to support this theory. Here, we studied a transgenic mouse carrying the HD mutation with a repeat of 50 CAGs (R6/2_50) that is within the pathological range of repeats causing adult-onset disease in humans. R6/2_50 mice develop characteristic HD brain aggregate pathology, with aggregates appearing predominantly in the striatum and cortex. However, they show few signs of disease in their lifetime. On the contrary, R6/2_50 mice appear to benefit from carrying the mutation. They have extended lifespans compared to wildtype (WT) mice, and male mice show enhanced fecundity. Furthermore, R6/2_50 mice outperform WT mice on the rotarod and show equal or better performance in the two choice discrimination task than WT mice. This novel mouse line provides direct experimental evidence that, although the HD mutation causes a fatal neurodegenerative disorder, there may be premorbid benefits of carrying the mutation.

Subcellular Localization And Formation Of Huntingtin Aggregates Correlates With Symptom Onset And Progression In A Huntington’S Disease Model

“…The work presented in this study contributes to a larger data set showing that the relationship between CAG repeat length and disease progression in R6/2 mice is complex, with phenotypes generally worsening with increasing CAG repeat length up to ∼150 CAGs, after which phenotypes improve as the CAG repeat length increases further ( Dragatsis et al , 2009 ; Morton et al , 2009 ; Cummings et al , 2012 ; Morton et al , 2019 ). The level of huntingtin expression at both RNA and protein levels was lower in R6/2 mice with expansions in 400 CAG range as opposed to 150 CAGs ( Dragatsis et al , 2009 ), consistent with the prediction that unusual DNA structures formed by super-long CAG repeats might impair transcription ( Duzdevich et al , 2011 ).…”

Increased plasma melatonin in presymptomatic Huntington disease sheep (Ovis aries): Compensatory neuroprotection in a neurodegenerative disease?

“…Nevertheless, this raises the intriguing possibility that the increase in melatonin in the sheep is part of a compensatory process in the presymptomatic HD brain that confers endogenous neuroprotection against the mutant protein. There is considerable evidence for the existence of such a phenomenon in presymptomatic HD mice that, despite ongoing expression of the mutation that eventually causes disease, are less susceptible to neurotoxins than control mice . Melatonin, with its well‐documented neuroprotective properties, is a prime candidate for playing a role in such autoprotection.…”

“…Finally, an intriguing possibility is that melatonin may not be coming from the pineal itself, but may be being produced directly by mitochondria in the brain . The relevance of this to HD is not yet clear, although it is interesting to note that there is increased energy metabolism in presymptomatic HD mice, and they are also more resistant to mitochondrial toxins at presymptomatic stages …”

The Contribution of Somatic Expansion of the CAG Repeat to Symptomatic Development in Huntington’s Disease: A Historical Perspective

“…Simply put, mice with small germline CAG expansions in the range typically observed in humans do not develop an overt HD phenotype during their lifetime [245,246]. HD mice with larger germline expansions typically beyond the length that is observed even in most juvenile HD cases (>80 repeats), can display robust HD phenotypes in a matter of months (e.g., [163,167,168]).…”

“…One of the primary reasons that more definitive data directly linking somatic expansion and disease pathology in HD models has been difficult to generate relates to the length of the CAG repeat in mice necessary to generate sufficient levels of somatic expansion and/or a disease phenotype during the lifetime of a mouse, or the even shorter length of a typical project grant. Simply put, mice with small germline CAG expansions in the range typically observed in humans do not develop an overt HD phenotype during their lifetime [ 245, 246 ]. HD mice with larger germline expansions typically beyond the length that is observed even in most juvenile HD cases (>80 repeats), can display robust HD phenotypes in a matter of months (e.g., [ 163, 167, 168 ]).…”