Huntingtin Is Required for Normal Excitatory Synapse Development in Cortical and Striatal Circuits

McKinstry, Spencer U.; Karadeniz, Yonca; Worthington, Atesh; Hayrapetyan, VY; Ozlu, M. Ilcim; Serafin-Molina, K; Risher, W. Christopher; Ustunkaya, Tuna; Dragatsis, Ioannis; Zeitlin, Scott; Hh, Yin; Eroğlu, Çağla

doi:10.1523/jneurosci.4699-13.2014

Cited by 131 publications

(157 citation statements)

References 68 publications

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“…The differences in learning and memory phenotypes between these mice suggest that the polyQ and the PRR could potentially modulate each other's effects on spatial learning and memory. an effect of mHtt expression on age-related synapse loss in HD mouse models [42,43,95]. Conditional loss of Htt expression using Emx1-Cre in the developing CNS results in an initial increase in corticostriatal and thalamostriatal synapses [95].…”

Section: Discussionmentioning

confidence: 99%

“…an effect of mHtt expression on age-related synapse loss in HD mouse models [42,43,95]. Conditional loss of Htt expression using Emx1-Cre in the developing CNS results in an initial increase in corticostriatal and thalamostriatal synapses [95]. However, synapse numbers in older Htt conditional knock-out brains were not examined; therefore, it is not known if early increases in synaptogenesis could result in later age-related phenotypes.…”

Section: Discussionmentioning

confidence: 99%

“…HTT also interacts with several Cytomatrix at Active Zone (CAZ) proteins in the pre-synaptic terminal including Bassoon, Piccolo, and Ahnak that modulate vesicular endo-and exocytosis [94]. When Htt is conditionally inactivated in cortical neurons, an increased number of Vglut1 + PSD-95 + corticostriatal synapses can be detected in the dorsal striatum of 21-day-old mice, while an increase in both corticostriatal synapses and Vglut2 + PSD-95 + thalamostriatal synapses can be observed in 5-week-old mice [95]. These data suggest that there is a role for Htt in synaptic development and maintenance.…”

Section: Wild Type Huntington Functionsmentioning

confidence: 99%

“…Recent work has also shown that loss of Htt expression during CNS development results in significant synaptic deficits [95]. When Htt is conditionally knocked out in the forebrains of mice, both corticostriatal and thalamostriatal synapse numbers in the dorsal striatum are altered [95].…”

Section: δN17-httmentioning

confidence: 99%

“…When Htt is conditionally knocked out in the forebrains of mice, both corticostriatal and thalamostriatal synapse numbers in the dorsal striatum are altered [95]. Additionally, Htt modulates clustering of PSD-95, which has been shown to modulate LTP and LTD and subsequently affect spatial learning and memory [40].…”

Section: δN17-httmentioning

confidence: 99%

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Structure/Function Analysis of the Huntingtin N-terminus Encoded by Htt Exon 1 Using Knock-In Mouse Models

André¹

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Huntington's disease (HD) is a neurodegenerative disorder that effects up to 1 in every 10,000 people and it is caused by an expansion of the polyglutamine (polyQ) stretch within the Huntingtin (HTT) protein [1]. The HTT polyQ in mammals is flanked by a highly conserved 17 amino acid N-terminal domain (N17), and a proline-rich region (PRR) [2][3][4]. The PRR is a binding site for many , and the N17 domain regulates several normal HTT functions, including HTT's ability to associate with membranes and organelles [8,9]. iv Acknowledgements I would first and foremost like to thank Scott Zeitlin and Jeh-Ping Liu for their scientific guidance, technical expertise and continual support. Thank you for always pushing me to be a better scientist, and for your patience during the times when things were not working out the way we wanted. I would also like to thank my committee

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Wild Type Huntington Functionsmentioning

confidence: 99%

Section: δN17-httmentioning

confidence: 99%

Section: δN17-httmentioning

confidence: 99%

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Structure/Function Analysis of the Huntingtin N-terminus Encoded by Htt Exon 1 Using Knock-In Mouse Models

André¹

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Huntingtin geneCAGrepeat size affects autism risk: Family‐based and case–control association study

Piras

Picinelli²,

Iennaco

et al. 2020

American J of Med Genetics Pt B

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The Huntingtin (HTT) gene contains a CAG repeat in exon 1, whose expansion beyond 39 repeats consistently leads to Huntington's disease (HD), whereas normal‐to‐intermediate alleles seemingly modulate brain structure, function and behavior. The role of the CAG repeat in Autism Spectrum Disorder (ASD) was investigated applying both family‐based and case–control association designs, with the SCA3 repeat as a negative control. Significant overtransmission of “long” CAG alleles (≥17 repeats) to autistic children and of “short” alleles (≤16 repeats) to their unaffected siblings (all p < 10−5) was observed in 612 ASD families (548 simplex and 64 multiplex). Surprisingly, both 193 population controls and 1,188 neurological non‐HD controls have significantly lower frequencies of “short” CAG alleles compared to 185 unaffected siblings and higher rates of “long” alleles compared to 548 ASD patients from the same families (p < .05–.001). The SCA3 CAG repeat displays no association. “Short” HTT alleles seemingly exert a protective effect from clinically overt autism in families carrying a genetic predisposition for ASD, while “long” alleles may enhance autism risk. Differential penetrance of autism‐inducing genetic/epigenetic variants may imply atypical developmental trajectories linked to HTT functions, including excitation/inhibition imbalance, cortical neurogenesis and apoptosis, neuronal migration, synapse formation, connectivity and homeostasis.

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Are we listening to everything the PARK genes are telling us?

Benson

Huntley

2019

J of Comparative Neurology

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The cardinal motor symptoms that define Parkinson's disease (PD) clinically have been recognized for over 200 years. That these symptoms arise following the loss of dopamine neurons in the substantia nigra has been known for the last 50. These long-established facts have fueled a broadly held expectation that degenerating dopaminergic neurons alone hold the key to understanding and curing PD. This prevalent expectation is at odds with the observation that many nonmotor symptoms, including depression and cognitive inflexibility among others, can appear years earlier than the overt dopaminergic neuron degeneration that drives motor abnormalities and are not improved by levodopa treatment. Thus, preserving or rescuing dopamine neuron health and function is of paramount importance, but this alone fails to capture the underlying neurobiology of earlier-appearing nonmotor symptoms. Insight into the complete landscape of disease-related abnormalities and the context in which they arise can be gleaned from a more comprehensive consideration of the PARK genes that are known to cause PD. Here, we make the case that a full incorporation of research showing when and where PARK genes are expressed as well as the impact of gene mutation on function throughout life, in tandem with research studying how dopaminergic neuron degeneration begins, is essential for a full understanding of the multi-dimensional etiology of PD. A broad view may also reveal something about long-term adjustments cells and systems make in response to gene mutation and help to identify mechanisms conferring the resilience or susceptibility of some cells and systems over others. K E Y W O R D Scritical periods, development, nonmotor symptoms, PARK genes, Parkinson's disease, protein degradation, protein trafficking

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Huntingtin Is Required for Normal Excitatory Synapse Development in Cortical and Striatal Circuits

Cited by 131 publications

References 68 publications

Structure/Function Analysis of the Huntingtin N-terminus Encoded by Htt Exon 1 Using Knock-In Mouse Models

Structure/Function Analysis of the Huntingtin N-terminus Encoded by Htt Exon 1 Using Knock-In Mouse Models

Huntingtin geneCAGrepeat size affects autism risk: Family‐based and case–control association study

Are we listening to everything the PARK genes are telling us?

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