Decreased Lin7b expression in layer 5 pyramidal neurons may contribute to impaired corticostriatal connectivity in huntington disease.
Motor dysfunction, cognitive impairment, and regional cortical atrophy indicate cerebral cortical involvement in Huntington disease (HD). To address the hypothesis that abnormal corticostriatal connectivity arises from polyglutamine-related alterations in cortical gene expression, we isolated layer 5 cortical neurons by laser-capture microdissection and analyzed transcriptome-wide mRNA changes in them. Enrichment of transcription factor mRNAs including foxp2, tbr1, and neuroD6, and neurotransmission- and plasticity-related RNAs including sema5A, pclo, ntrk2, cntn1, and Lin7b were observed. Layer 5 motor cortex neurons of transgenic R6/2 HD mice also demonstrated numerous transcriptomic changes, including decreased expression of mRNAs encoding the Lin7 homolog b ([Lin7b] also known as veli-2 and mals2). Decreases in LIN7B and CNTN1 RNAs were also detected in human HD layer 5 motor cortex neurons. Lin7 homolog b, a scaffold protein implicated in synaptic plasticity, neurite outgrowth, and cellular polarity, was decreased at the protein level in layer 5 cortical neurons in R6/2 mice and human HD brains. Decreases in Lin7b and Lin7a mRNAs were detected in R6/2 cortex as early as 6 weeks of age, suggesting that this is an early pathogenetic event. Thus, decreased cortical LIN7 expression may contribute to abnormal corticostriatal connectivity in HD.
Zucker
Birgit
B
Department of Neurology, University Hospital Freiburg, Freiburg, Germany.
Kama
Jibrin A
JA
Kuhn
Alexandre
A
Thu
Doris
D
Orlando
Lianna R
LR
Dunah
Anthone W
AW
Gokce
Ozgun
O
Taylor
David M
DM
Lambeck
Johann
J
Friedrich
Bernd
B
Lindenberg
Katrin S
KS
Faull
Richard L M
RL
Weiller
Cornelius
C
Young
Anne B
AB
Luthi-Carter
Ruth
R
D000818:Animals; D002540:Cerebral Cortex / Q000166:cytology / Q000473:pathology / Q000502:physiology; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000473:pathology / Q000503:physiopathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis; D009434:Neural Pathways / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
C486532:LIN7A protein, human; C114671:LIN7B protein, human; C114670:Lin7a protein, mouse; C485432:Lin7b protein, mouse; D008565:Membrane Proteins; D033921:Vesicular Transport Proteins