A spastic paraplegia mouse model reveals REEP1-dependent ER shaping.
Axonopathies are a group of clinically diverse disorders characterized by the progressive degeneration of the axons of specific neurons. In hereditary spastic paraplegia (HSP), the axons of cortical motor neurons degenerate and cause a spastic movement disorder. HSP is linked to mutations in several loci known collectively as the spastic paraplegia genes (SPGs). We identified a heterozygous receptor accessory protein 1 (REEP1) exon 2 deletion in a patient suffering from the autosomal dominantly inherited HSP variant SPG31. We generated the corresponding mouse model to study the underlying cellular pathology. Mice with heterozygous deletion of exon 2 in Reep1 displayed a gait disorder closely resembling SPG31 in humans. Homozygous exon 2 deletion resulted in the complete loss of REEP1 and a more severe phenotype with earlier onset. At the molecular level, we demonstrated that REEP1 is a neuron-specific, membrane-binding, and membrane curvature-inducing protein that resides in the ER. We further show that Reep1 expression was prominent in cortical motor neurons. In REEP1-deficient mice, these neurons showed reduced complexity of the peripheral ER upon ultrastructural analysis. Our study connects proper neuronal ER architecture to long-term axon survival.
Christian
C
Beetz
Nicole
N
Koch
Mukhran
M
Khundadze
Geraldine
G
Zimmer
Sandor
S
Nietzsche
Nicole
N
Hertel
Antje-Kathrin
AK
Huebner
Rizwan
R
Mumtaz
Michaela
M
Schweizer
Elisabeth
E
Dirren
Kathrin N
KN
Karle
Andrey
A
Irintchev
Victoria
V
Alvarez
Christoph
C
Redies
Martin
M
Westermann
Ingo
I
Kurth
Thomas
T
Deufel
Michael M
MM
Kessels
Britta
B
Qualmann
Christian A
CA
Hübner
D000818:Animals; D001483:Base Sequence; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology; D005091:Exons; D005684:Gait; D006801:Humans; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D017384:Sequence Deletion; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000473:pathology; D013116:Spinal Cord / Q000473:pathology
D026901:Membrane Transport Proteins; C495318:REEP1 protein, human