Postnatal and adult consequences of loss of huntingtin during development: Implications for Huntington's disease

Abstract

The mutation in huntingtin (mHtt) leads to a spectrum of impairments in the developing forebrain of Huntington’s disease (HD) mouse models. Whether these developmental alterations are due to loss- or gain-of-function mechanisms and contribute to HD pathogenesis is unknown. We examined the role of selective loss of huntingtin (Htt) function during development on postnatal vulnerability to cell death. We employed mice expressing very low levels of Htt throughout embryonic life to postnatal day 21 (Hdhd•hyp). We demonstrated that Hdhd•hyp mice exhibit: (1) late-life striatal and cortical neuronal degeneration; (2) neurological and skeletal muscle alterations; and (3) white matter tract impairments and axonal degeneration. Hdhd•hyp embryos also exhibited subpallial heterotopias, aberrant striatal maturation and deregulation of gliogenesis. These results indicate that developmental deficits associated with Htt functions render cells present at discrete neural foci increasingly susceptible to cell death, thus implying the potential existence of a loss-of-function developmental component to HD pathogenesis.

Intrinsic mutant HTT-mediated defects in oligodendroglia cause myelination deficits and behavioral abnormalities in Huntington disease

“…Emerging evidence suggests that neurodevelopment may be altered in HD (41), including several aspects related to oligodendroglia. For example, mice expressing reduced levels of Htt throughout development exhibit OPC maturation abnormalities and white matter tract impairments (42). OPCs isolated from neonatal HD mouse brains and derivative oligodendrocytes show deficits in the levels of myelin-related genes (8).…”

Neuropathological Comparison of Adult Onset and Juvenile Huntington’s Disease with Cerebellar Atrophy: A Report of a Father and Son

“…Most mouse models of HD have traditionally recapitulated the neuropathologic hallmarks of AOHD, often lacking features more typical of JHD, such as significant cerebellar involvement (17); however, more recent models using much larger CAG repeats of HTT have highlighted cerebellar pathology (18), which may indicate that features more common to JHD, such as cerebellar involvement, may at least in part be dependent on greater repeat length. Additionally, a mouse model in which loss of normal huntingtin protein was targeted specifically to the period of neural development showed characteristic features of JHD, such as hindlimb stiffness, seizures, and cerebellar involvement, suggesting that the effects of loss of normal huntingtin function may be somewhat related to neurodevelopmental processes (19). Indeed, huntingtin is known to interact with a number of different proteins involved in a variety of processes important for neurodevelopment, such as transcription, trafficking and endocytosis, signaling, and metabolism (20).…”

“…Indeed, huntingtin is known to interact with a number of different proteins involved in a variety of processes important for neurodevelopment, such as transcription, trafficking and endocytosis, signaling, and metabolism (20). It has been hypothesized that in JHD there is a more severe disruption in the interactions between huntingtin and its protein partners due to both a loss of function of the pathologic allele as well as a gain of toxic function against the functioning of the normal allele due to the marked trinucleotide expansion (19). This could ultimately lead to more developmentally important pathways affected in JHD than in AOHD, which may, in part, explain the variable presentation seen in this case of a father and a son with HD.…”

Developmental origins of cortical hyperexcitability in Huntington's disease: Review and new observations

“…In addition, as mHTT is also abundant in striatum, it would be important to know if striatal compartmental organization, that is, striosome and matrix, is affected. For example, studies have shown that reduced expression of wildtype HTT during development can induce profound changes in striatal organization, including heterotopias that share striosome and matrix identities (Arteaga‐Bracho et al, ). Finally, circuit organization in brain stem and thalamic regions, such as the inferior colliculus, should be examined to determine if abnormal development could explain the exquisite susceptibility of R6/2 mice to manifest audiogenic seizures.…”

“…Indeed, expression of mHTT during early development is sufficient to produce a permanent HD phenotype even if expression is terminated at P21. Furthermore, developmental deficits associated with HTT function render cells more susceptible to degeneration (Arteaga‐Bracho et al, ; Molero et al, ).…”