Calcium signaling and neurodegenerative diseases

Abstract

Neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and spinocerebellar ataxias (SCAs), present an enormous medical, social, financial and scientific problem. Recent evidence indicates that neuronal calcium (Ca2+) signaling is abnormal in many of these disorders. Similar, but less severe, changes in neuronal Ca2+ signaling occur as a result of the normal aging process. The role of aberrant neuronal Ca2+ signaling in the pathogenesis of neurodegenerative disorders is discussed here. The potential utility of Ca2+ blockers for treatment of these disorders is also highlighted. It is reasoned that Ca2+ blockers will be most beneficial clinically when used in combination with other disease-specific therapeutic approaches.

Figure 1

The model of Ca²⁺ dysregulation in AD. Sequential cleavages of β-amyloid precursor protein (APP) by β-secretase (β) and γ-secretase (γ) generate amyloid β-peptide (Aβ). Aβ forms oligomers, which can insert into the plasma membrane and form Ca²⁺-permeable pores. The association of Aβ oligomers with the plasma membrane is facilitated by binding to surface phosphatidylserine (PtdS); age and Ca²⁺-related mitochondrial impairment leads to ATP depletion and might trigger flipping of PtdS from the inner portion of the plasma membrane to the cell surface. Reduction in ATP levels and loss of membrane integrity causes membrane depolarization, which leads to facilitation of Ca²⁺ influx through NMDAR and VGCC. Aβ oligomers can also affect activity of NMDAR, AMPAR and VGCC directly. Glutamate stimulates activation of mGluR1/5 receptors, production of InsP₃ and InsP₃-mediated Ca²⁺ release from the ER. Presenilins (PS) function as an ER Ca²⁺-leak channels and many FAD mutations impair Ca²⁺-leak-channel function of PS, resulting in excessive accumulation of Ca²⁺ in the ER. Increased ER Ca²⁺ levels result in enhanced Ca²⁺ release through InsP₃-gated InsP₃R1 and Ca²⁺-gated RyanR2. PS might also modulate activity of InsP₃R, RyanR and SERCA pump directly. Elevated cytosolic Ca²⁺ levels result in the activation of calcineurin (CaN) and calpains and lead to facilitation of LTD, inhibition of LTP, modification of neuronal cytoskeleton, synaptic loss and neuritic atrophy. Excessive Ca²⁺ is taken up by mitochondria through mitochondrial Ca²⁺ uniporter (MCU), eventually leading to opening of mitochondrial permeability-transition pore (mtPTP) and apoptosis. The NMDAR inhibitor memantine (MMT) is approved for the treatment of AD and the NR2B-specific antagonist EVT-101 was recently developed for AD treatment. ‘CNS-optimized’ L-type VGCC inhibitor MEM-1003, putative ‘mitochondrial agent’ Dimebon and ‘mitochondrial energizer’ Ketasyn are in clinical trials for AD. Adapted from [6].

Figure 2

The model of Ca²⁺ dysregulation in PD. Continuous Ca²⁺ influx to SNc neurons is mediated by Ca_V1.3 L-type voltage-gated Ca²⁺ channels (Ca_V1.3). In response to glutamate, Ca²⁺ influx is mediated by NMDA receptors (NMDAR). Alpha-synuclein forms aggregates (protofibrils) which may form Ca²⁺-permeable channels in the plasma membrane. Elevated cytosolic Ca²⁺ is transported into mitochondria through the activity of mitochondrial Ca²⁺ uniporter (MCU). Dopamine (DA) is generated from L-tyrosine by the action of tyrosine hydroxylase (TH) and is loaded into the synaptic vesicles by the activity of the DA/H⁺ cotransporter (VMAT2). Cytosolic DA is oxidized to 6-hydroxy-DA, which causes damage to proteins and mitochondria by oxidative stress. The products of DA oxidation accumulate as neuromelanin (NM). Cumulative damage to mitochondria resulting from Ca²⁺ overload and DA-mediated oxidative stress leads to an opening of mtPTP and apoptotic cell death of SNc neurons in PD. An importance of mitochondria is highlighted by several mitochondria-related genes (e.g. LRRK2, PINK1, DJ-1, Parkin), which are mutated in familial PD. In a chemical model of PD, the toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is converted to the 1-methyl-4-phenylpyridinium (MPP⁺) by the glial enzyme monoamine oxidase B (MAO-B). MPP⁺ enters SNc neurons and potently inhibits mitochondrial complex I, causing selective cell death of SNc neurons. The US FDA-approved treatment for PD is levodopa (L-dopa), which is converted to DA by aromatic L-amino acid decarboxylase (DCC) inside SNc neurons. Generated DA is loaded to synaptic vesicles and alleviates symptoms of PD temporarily. The drugs tested or in PD clinical trials currently are ‘mitochondrial stabilizers’ (creatine, CoQ10, MitoQ), NMDAR antagonist memantine (MMT), antiglutamate agent riluzole and L-type VGCC inhibitor isradipine.

Figure 3

The model of excitotoxicity and Ca²⁺ dysregulation in ALS. The pathogenic cascade in ALS involves interactions among activated microglia, astrocytes and motor neurons (MNs). In an experimental situation, microglia can be activated by antiserum collected from ALS patients (ALS IgG). Activated microglia release pro-inflammatory factors TNF-α, NO and O₂⁻. Activated microglia also release large amounts of glutamate, which causes activation of AMPA and NMDA receptors on MNs. Activated microglia also release D-serine, which further sensitizes NMDAR to glutamate activation. Astrocytes express glutamate-uptake transporter EAAT2, which is involved in clearing glutamate from the extracellular space. Ca²⁺ influx by Ca²⁺-permeable AMPA receptors and NMDA receptors results in mitochondrial Ca²⁺ overload, mitochondrial swelling, opening of mitochondrial permeability-transition pore (mtPTP) and apoptosis of MNs. Mutant SOD1 binds to MN mitochondria and further impairs their ability to handle Ca²⁺ load. Antiglutamate agent riluzole is approved by the US FDA for treatment of ALS. NMDAR antagonist memantine (MMT) and ‘mitochondrial stabilizers’ creatine and CoQ10 are in ALS clinical trials currently.

Figure 4

The model of Ca²⁺ dysregulation in HD. In HD MSN, the Htt^exp perturbs Ca²⁺ signaling through several synergistic mechanisms. Htt^exp enhances function of NR2B-containing NMDAR, probably by promoting trafficking to the plasma membrane. Htt^exp binds strongly to the InsP₃R1C terminus and sensitizes the InsP₃R1 to activation by InsP₃. The low levels of glutamate released from corticostriatal projection neurons lead to supranormal Ca²⁺ influx by NMDAR and Ca²⁺ release through the InsP₃R1. Additional Ca²⁺ influx to MSN is mediated by voltage-gated Ca²⁺ channels (VGCCs). Dopamine released from midbrain dopaminergic neurons stimulates D1-class and D2-class DARs, which are expressed abundantly in MSNs. D1-class DARs are coupled to activation of adenyl cyclase, increase in cAMP levels and activation of PKA. PKA potentiates glutamate-induced Ca²⁺ signals by facilitating the activity of NMDAR and InsP₃R1. D2 receptors are coupled directly to InsP₃ production and activation of InsP₃R1. Supranormal Ca²⁺ signals activate calpain, which cleave Htt^exp and other substrates. Excessive cytosolic Ca²⁺ signals result in mitochondrial Ca²⁺ uptake by MCU, which eventually triggers mtPTP opening and apoptosis. The mitochondrial Ca²⁺ handling is further destabilized by direct association of Htt^exp with mitochondria. Antidopamine agent tetrabenazine (TBZ) is approved by the US FDA for symptomatic treatment of HD. NMDAR antagonist memantine (MMT), putative ‘mitochondrial agent’ Dimebon and ‘mitochondrial stabilizers’ creatine and CoQ10 are tested in HD clinical trials. Antiglutamate agent riluzole was tested and failed [66]. Adapted from [77].