Widespread brain parenchymal HMGB1 and NF-κB neuroinflammatory responses upon cortical spreading depolarization in familial hemiplegic migraine type 1 mice

Familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) are allelic disorders caused by mutations in the CACNA1A gene on chromosome 19p13. It is well described that FHM1 can present with cerebellar signs, but parkinsonism has not previously been reported in FHM1 or EA2 even though parkinsonism has been described in SCA6. We report a 63-year-old woman with FHM1 caused by an R583Q mutation in the CACNA1A gene, clinically presenting with migraine and permanent cerebellar ataxia. Since the age of 60 years, the patient also developed parkinsonism with rigidity, bradykinesia and a resting tremor. An MRI showed a normal substantia nigra, but a bilateral loss of substance in the basal ganglia, which is in contrast to the typically normal MRI in idiopathic Parkinson's disease. Dopamine transporter (DAT) imaging with single-photon emission computed tomography demonstrated a decreased DAT-binding potential in the putamen. We wish to draw attention to FHM1 associated with parkinsonism; however, whether the reported case is a consequence of FHM1 being allelic to SCA6, unknown modifiers to the specific R583Q CACNA1A mutation or idiopathic Parkinson's disease remains unanswered.

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The familial hemiplegic migraine type 1 mutation K1336E affects direct G protein-mediated regulation of neuronal P/Q-type Ca2+ channels

Cephalalgia ◽

10.1177/0333102412475236 ◽

2013 ◽

Vol 33 (6) ◽

pp. 398-407 ◽

Cited By ~ 8

Author(s):

Edgar Garza-López ◽

Ricardo González-Ramírez ◽

María A Gandini ◽

Alejandro Sandoval ◽

Ricardo Felix

Keyword(s):

G Protein ◽

Familial Hemiplegic Migraine ◽

Inactivation Kinetics ◽

Missense Mutations ◽

Hemiplegic Migraine ◽

Gene Encoding ◽

Dominant Form ◽

Hek 293 ◽

Autosomal Dominant Form

Background Familial hemiplegic migraine type 1 (FHM-1) is an autosomal dominant form of migraine with aura characterized by recurrent migraine, hemiparesis and ataxia. FHM-1 has been linked to missense mutations in the CACNA1A gene encoding the pore-forming subunit of the neuronal voltage-gated P/Q-type Ca2+ channel (CaV2.1α1). Methods Here, we explored the effects of the FHM-1 K1336E mutation on G protein-dependent modulation of the recombinant P/Q-type channel. The mutation was introduced into the human CaV2.1α1 subunit and its functional consequences investigated after heterologous expression in HEK-293 cells using patch-clamp recordings. Results Functional analysis of the K1336E mutation revealed a reduction of Ca2+ current densities, a ∼10 mV left-shift in the current-voltage relationship, and the slowing of current inactivation kinetics. When co-expressed along with the human μ-opioid receptor, application of the agonist DAMGO inhibited whole-cell currents through both the wild-type and the mutant channels. Prepulse facilitation was also reduced by the K1336E mutation. Likewise, the kinetic analysis of the onset and decay of facilitation showed that the mutation affects the apparent dissociation and reassociation rates of the Gβγ dimer from the channel complex. Conclusions These results suggest that the extent of G-protein-mediated inhibition is significantly reduced in the K1336E mutant CaV2.1 Ca2+ channels. This alteration would contribute to render the neuronal network hyperexcitable, possibly as a consequence of reduced presynaptic inhibition, and may help to explain some aspects of the FHM-1 pathophysiology.

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Hyperpolarization-activated current I h in mouse trigeminal sensory neurons in a transgenic mouse model of familial hemiplegic migraine type-1

Neuroscience ◽

10.1016/j.neuroscience.2017.03.033 ◽

2017 ◽

Vol 351 ◽

pp. 47-64 ◽

Cited By ~ 4

Author(s):

Francesca Eroli ◽

Sandra Vilotti ◽

Arn M.J.M. van den Maagdenberg ◽

Andrea Nistri

Keyword(s):

Mouse Model ◽

Transgenic Mouse ◽

Sensory Neurons ◽

Familial Hemiplegic Migraine ◽

Transgenic Mouse Model ◽

Hemiplegic Migraine ◽

Hyperpolarization Activated Current

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Time course of downbeat positioning nystagmus in familial hemiplegic migraine type 1 treated with acetazolamide

Journal of the Neurological Sciences ◽

10.1016/j.jns.2016.07.020 ◽

2016 ◽

Vol 368 ◽

pp. 206-208 ◽

Cited By ~ 2

Author(s):

Masanobu Suzuki ◽

Keishi Fujiwara ◽

Takashi Tsubuku ◽

Ichiro Yabe ◽

Hidenao Sasaki ◽

...

Keyword(s):

Time Course ◽

Familial Hemiplegic Migraine ◽

Hemiplegic Migraine ◽

Downbeat Positioning Nystagmus

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