Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0002736 (
amyotrophic lateral sclerosis
)
19,048
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Members of the SCY1-like (SCYL) family of protein kinases are evolutionarily conserved and ubiquitously expressed proteins characterized by an N-terminal pseudokinase domain, centrally located Huntingtin, elongation factor 3, protein phosphatase 2A, yeast kinase TOR1 repeats, and an overall disorganized C-terminal segment. In mammals, three family members encoded by genes
Scyl1
,
Scyl2
, and
Scyl3
have been described. Studies have pointed to a role for SCYL1 and SCYL2 in regulating neuronal function and viability in mice and humans, but little is known about the biological function of
SCYL3
. Here, we show that the biochemical and cell biological properties of
SCYL3
are similar to those of SCYL1 and both proteins work in conjunction to maintain motor neuron viability. Specifically, although lack of
Scyl3
in mice has no apparent effect on embryogenesis and postnatal life, it accelerates the onset of the motor neuron disorder caused by
Scyl1
deficiency. Growth abnormalities, motor dysfunction, hindlimb paralysis, muscle wasting, neurogenic atrophy, motor neuron degeneration, and loss of large-caliber axons in peripheral nerves occurred at an earlier age in
Scyl1
/S
cyl3
double-deficient mice than in
Scyl1
-deficient mice. Disease onset also correlated with the mislocalization of TDP-43 in spinal motor neurons, suggesting that SCYL1 and
SCYL3
regulate TDP-43 proteostasis. Together, our results demonstrate an overlapping role for SCYL1 and
SCYL3
in vivo
and highlight the importance the SCYL family of proteins in regulating neuronal function and survival. Only male mice were used in this study.
SIGNIFICANCE STATEMENT
SCYL1 and SCYL2, members of the SCY1-like family of pseudokinases, have well established roles in neuronal function. Herein, we uncover the role of
SCYL3
in maintaining motor neuron viability. Although targeted disruption of
Scyl3
in mice had little or no effect on embryonic development and postnatal life, it accelerated disease onset associated with the loss of
Scyl1
, a novel motor neuron disease gene in humans.
Scyl1
and
Scyl3
double-deficient mice had neuronal defects characteristic of
amyotrophic lateral sclerosis
, including TDP-43 pathology, at an earlier age than did
Scyl1
-deficient mice. Thus, we show that SCYL1 and
SCYL3
play overlapping roles in maintaining motor neuronal viability
in vivo
and confirm that SCYL family members are critical regulators of neuronal function and survival.
...
PMID:Overlapping Role of SCYL1 and SCYL3 in Maintaining Motor Neuron Viability. 2943 92
