Motor neurons with differential vulnerability to degeneration show distinct protein signatures in health and ALS

TY - JOUR

T1 - Motor neurons with differential vulnerability to degeneration show distinct protein signatures in health and ALS

AU - Comley, L.

AU - Allodi, I.

AU - Nichterwitz, S.

AU - Nizzardo, M.

AU - Simone, C.

AU - Corti, S.

AU - Hedlund, E.

PY - 2015

Y1 - 2015

N2 - The lethal disease amyotrophic lateral sclerosis (ALS) is characterized by the loss of somatic motor neurons. However, not all motor neurons are equally vulnerable to disease; certain groups are spared, including those in the oculomotor nucleus controlling eye movement. The reasons for this differential vulnerability remain unknown. Here we have identified a protein signature for resistant oculomotor motor neurons and vulnerable hypoglossal and spinal motor neurons in mouse and man and in health and ALS with the aim of understanding motor neuron resistance. Several proteins with implications for motor neuron resistance, including GABAA receptor α1, guanylate cyclase soluble subunit alpha-3 and parvalbumin were persistently expressed in oculomotor neurons in man and mouse. Vulnerable motor neurons displayed higher protein levels of dynein, peripherin and GABAA receptor α2, which play roles in retrograde transport and excitability, respectively. These were dynamically regulated during disease and thus could place motor neurons at an increased risk. From our analysis is it evident that oculomotor motor neurons have a distinct protein signature compared to vulnerable motor neurons in brain stem and spinal cord, which could in part explain their resistance to degeneration in ALS. Our comparison of human and mouse shows the relative conservation of signals across species and infers that transgenic SOD1G93A mice could be used to predict mechanisms of neuronal vulnerability in man.

AB - The lethal disease amyotrophic lateral sclerosis (ALS) is characterized by the loss of somatic motor neurons. However, not all motor neurons are equally vulnerable to disease; certain groups are spared, including those in the oculomotor nucleus controlling eye movement. The reasons for this differential vulnerability remain unknown. Here we have identified a protein signature for resistant oculomotor motor neurons and vulnerable hypoglossal and spinal motor neurons in mouse and man and in health and ALS with the aim of understanding motor neuron resistance. Several proteins with implications for motor neuron resistance, including GABAA receptor α1, guanylate cyclase soluble subunit alpha-3 and parvalbumin were persistently expressed in oculomotor neurons in man and mouse. Vulnerable motor neurons displayed higher protein levels of dynein, peripherin and GABAA receptor α2, which play roles in retrograde transport and excitability, respectively. These were dynamically regulated during disease and thus could place motor neurons at an increased risk. From our analysis is it evident that oculomotor motor neurons have a distinct protein signature compared to vulnerable motor neurons in brain stem and spinal cord, which could in part explain their resistance to degeneration in ALS. Our comparison of human and mouse shows the relative conservation of signals across species and infers that transgenic SOD1G93A mice could be used to predict mechanisms of neuronal vulnerability in man.

KW - Amyotrophic lateral sclerosis

KW - Motor neuron

KW - Neurodegeneration

KW - Oculomotor

KW - Selective vulnerability

U2 - 10.1016/j.neuroscience.2015.02.013

DO - 10.1016/j.neuroscience.2015.02.013

M3 - Journal article

C2 - 25697826

AN - SCOPUS:84923329869

SN - 0306-4522

VL - 291

SP - 216

EP - 229

JO - Neuroscience

JF - Neuroscience

ER -