Enhanced sensitivity of DJ-1-deficient dopaminergic neurons to energy metabolism impairment: role of Na+/K+ ATPase.
DJ-1 gene mutations lead to an inherited form of early-onset parkinsonism. The function of DJ-1 is unclear, though a neuroprotective role has been postulated. Electrophysiological recordings were made of striatal and dopaminergic nigral neurons both of wild-type (WT) and DJ-1-knockout (DJ-1(-/-)) mice. We assessed the responses of dopaminergic cells to combined oxygen and glucose deprivation (OGD), and to the mitochondrial toxin rotenone. OGD induced a membrane hyperpolarization in nigral neurons from WT mice. Similarly, rotenone hyperpolarized neurons and then a depolarization occurred. In DJ-1(-/-) mice, the OGD-induced hyperpolarization was significantly enhanced. Moreover, rotenone caused a shorter hyperpolarization followed by an irreversible depolarization. To evaluate the involvement of Na+/K+ ATPase, we tested ouabain, a Na+/K+ ATPase inhibitor, on two distinct neuronal subtypes. Compared to WT mice, in dopaminergic neurons from DJ-1(-/-) mice, ouabain induced rapid and irreversible membrane potential changes. Notably, this effect was observed at concentrations that were unable to produce membrane potential shifts on striatal spiny neurons, both from WT and DJ-1(-/-) mice. These findings suggest that DJ-1 loss-of-function enhances vulnerability to energy metabolism alterations, and that nigral neurons are particularly sensitive to Na+/K+ ATPase impairment.
Pisani
A
A
Clinica Neurologica, Dipartimento di Neuroscienze, Università Tor Vergata, Roma, Italy. pisani@uniroma2.it
Martella
G
G
Tscherter
A
A
Costa
C
C
Mercuri
N B
NB
Bernardi
G
G
Shen
J
J
Calabresi
P
P
D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000172:deficiency; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D015513:Oncogene Proteins / Q000172:deficiency* / Q000235:genetics; D009924:Organ Culture Techniques; D010042:Ouabain / Q000494:pharmacology; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D018408:Patch-Clamp Techniques; D054464:Peroxiredoxins; D000071617:Protein Deglycase DJ-1; D012402:Rotenone / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism*; D014475:Uncoupling Agents / Q000494:pharmacology
D004791:Enzyme Inhibitors; D015513:Oncogene Proteins; D014475:Uncoupling Agents; D012402:Rotenone; D010042:Ouabain; D054464:Peroxiredoxins; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1; D000254:Sodium-Potassium-Exchanging ATPase; D005947:Glucose; D004298:Dopamine