Perfluorooctanoic acid induces cardiac dysfunction in human induced pluripotent stem cell-derived cardiomyocytes.

Perfluorooctanoic acid (PFOA), commonly found in drinking water, leads to widespread exposure through skin contact, inhalation, and ingestion, resulting in detectable levels of PFOA in the bloodstream. In this study, we found that exposure to PFOA disrupts cardiac function in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). We observed reductions in field and action potentials in hiPSC-CMs exposed to PFOA. Furthermore, PFOA demonstrated a dose-dependent inhibitory effect on various ion channels, including the calcium, sodium, and potassium channels. Additionally, we noted dose-dependent inhibition of the expression of these ion channels in hiPSC-CMs following exposure to PFOA. These findings suggest that PFOA exposure can impair cardiac ion channel function and decrease the transcription of genes associated with these channels, potentially contributing to cardiac dysfunction such as arrhythmias. Our study sheds light on the electrophysiological and epigenetic consequences of PFOA-induced cardiac dysfunction, underscoring the importance of further research on the cardiovascular effects of perfluorinated compounds (PFCs).

Differential regulations of neural activity and survival in primary cortical neurons by PFOA or PFHpA.

Perfluorinated compounds (PFCs), organofluoride compounds comprising carbon-fluorine and carbon-carbon bonds, are used as water and oil repellents in textiles and pharmaceutical tablets; however, they are associated with potential neurotoxic effects. Moreover, the impact of PFCs on neuronal survival, activity, and regulation within the brain remains unclear. Additionally, the mechanisms through which PFCs induce neuronal toxicity are not well-understood because of the paucity of data. This study elucidates that perfluorooctanoic acid (PFOA) and perfluoroheptanoic acid (PFHpA) exert differential effects on the survival and activity of primary cortical neurons. Although PFOA triggers apoptosis in cortical neurons, PFHpA does not exhibit this effect. Instead, PFHpA modifies dendritic spine morphogenesis and synapse formation in primary cortical neuronal cultures, additionally enhancing neural activity and synaptic transmission. This research uncovers a novel mechanism through which PFCs (PFHpA and PFOA) cause distinct alterations in dendritic spine morphogenesis and synaptic activity, shedding light on the molecular basis for the atypical behaviors noted following PFC exposure. Understanding the distinct effects of PFHpA and PFOA could guide regulatory policies on PFC usage and inform clinical approaches to mitigate their neurotoxic effects, especially in vulnerable population.

Prenatal Di-methoxyethyl phthalate exposure impairs cortical neurogenesis and synaptic activity in the mice.

Di-methoxyethyl phthalate (DMEP) is a well-known environmentally prevalent endocrine disruptor and may be associated with neurodevelopmental disorders including attention deficit/hyperactivity disorder and intellectual disability. However, the regulatory mechanisms leading to these neurodevelopmental disorders are still poorly understood. Here, we demonstrate that prenatal DMEP exposure causes abnormal brain morphology and function in the mice. DMEP (50 mg/kg) was chronically administered to pregnant mice orally once a day starting on embryonic day 0 (E0) to breast-feeding cessation for the fetus. We found that prenatal DMEP exposure significantly reduced the number of neurons in the parietal cortex by impairing neurogenesis and gliogenesis during the developing cortex. Moreover, we found that prenatal DMEP exposure impaired dendritic spine architectures and synaptic activity in the parietal cortex. Finally, prenatal DMEP exposure in mice induces hyperactivity and reduces anxiety behaviors. Altogether, our study demonstrates that prenatal DMEP exposure leads to abnormal behaviors via impairment of neurogenesis and synaptic activity.

Bisphenol-A impairs synaptic formation and function by RGS4-mediated regulation of BDNF signaling in the cerebral cortex.

Bisphenol-A (BPA) is a representative endocrine disruptor, widely used in a variety of products including plastics, medical equipment and receipts. Hence, most people are exposed to BPA via the skin, digestive system or inhalation in everyday life. Furthermore, BPA crosses the blood-brain barrier and is linked to multiple neurological dysfunctions found in neurodegenerative and neuropsychological disorders. However, the mechanisms underlying BPA-associated neurological dysfunctions remain poorly understood. Here, we report that BPA exposure alters synapse morphology and function in the cerebral cortex. Cortical pyramidal neurons treated with BPA showed reduced size and number of dendrites and spines. The density of excitatory synapses was also decreased by BPA treatment. More importantly, we found that BPA disrupted normal synaptic transmission and cognitive behavior. RGS4 and its downstream BDNF/NTRK2 pathway appeared to mediate the effect of BPA on synaptic and neurological function. Our findings provide molecular mechanistic insights into anatomical and physiological neurotoxic consequences related to a potent endocrine modifier.

WDR5-HOTTIP Histone Modifying Complex Regulates Neural Migration and Dendrite Polarity of Pyramidal Neurons via Reelin Signaling.

WD-repeat domain 5 (WDR5), a core component of histone methyltransferase complexes, is associated with Kabuki syndrome and Kleefstra syndrome that feature intellectual disability and neurodevelopmental delay. Despite its critical status in gene regulation and neurological disorders, the role of WDR5 in neural development is unknown. Here we show that WDR5 is required for normal neuronal placement and dendrite polarization in the developing cerebral cortex. WDR5 knockdown led to defects in both entry into the bipolar transition of pyramidal neurons within the intermediate zone and radial migration into cortical layers. Moreover, WDR5 deficiency disrupted apical and basal polarity of cortical dendrites. Aberrant dendritic spines and synapses accompanied the dendrite polarity phenotype. WDR5 deficiency reduced expression of reelin signaling receptors, ApoER and VdldR, which were associated with abnormal H3K4 methylation and H4 acetylation on their promoter regions. Finally, an lncRNA, HOTTIP, was found to be a partner of WDR5 to regulate dendritic polarity and reelin signaling via histone modification. Our results demonstrate a novel role for WDR5 in neuronal development and provide mechanistic insights into the neuropathology associated with histone methyltransferase dysfunction.

Adipose stem cell-derived extracellular vesicles ameliorates corticosterone-induced apoptosis in the cortical neurons via inhibition of ER stress.

BACKGROUND: Corticosterone (CORT) can induce neuronal damage in various brain regions, including the cerebral cortex, the region implicated in depression. However, the underlying mechanisms of these CORT-induced effects remain poorly understood. Recently, many studies have suggested that adipose stem cell-derived extracellular vesicles (A-EVs) protect neurons in the brain. METHODS: To investigated neuroprotection effects of A-EVs in the CORT-induced cortical neurons, we cultured cortical neurons from E15 mice for 7 days, and the cultured cortical neurons were pretreated with different numbers (5 × 105-107 per mL) of A-EVs (A-EVs5, A-EVs6, A-EVs7) for 30 min followed by administration of 200 µM CORT for 24 h. RESULTS: Here, we show that A-EVs exert antiapoptotic effects by inhibiting endoplasmic reticulum (ER) stress in CORT-induced cortical neurons. We found that A-EVs prevented neuronal cell death induced by CORT in cultured cortical neurons. More importantly, we found that CORT exposure in cortical neurons resulted in increased levels of apoptosis-related proteins such as cleaved caspase-3. However, pretreatment with A-EVs rescued the levels of caspase-3. Intriguingly, CORT-induced apoptosis involved upstream activation of ER stress proteins such as GRP78, CHOP and ATF4. However, pretreatment with A-EVs inhibited ER stress-related protein expression. CONCLUSION: Our findings reveal that A-EVs exert antiapoptotic effects via inhibition of ER stress in CORT-induced cell death.

Butylparaben Induces the Neuronal Death Through the ER Stress-Mediated Apoptosis of Primary Cortical Neurons.

Butylparaben is an organic compound that is used as an antimicrobial preservative in cosmetics and can cause neurotoxicity. However, whether butylparaben induces neuronal death is unclear. In this study, we report that butylparaben exposure induced neuronal apoptosis mediated by ER stress in primary cortical neurons. We found that butylparaben significantly inhibited the viability of primary cortical neurons and led to lactate dehydrogenase (LDH) release from primary cortical neurons. Upon exposure to butylparaben, primary cortical neurons exhibited increased levels of apoptosis-related proteins such as Cleaved-caspase3 and Bax. Interestingly, butylparaben-induced activation of apoptosis involved the upstream activation of ER stress proteins such as GRP78, CHOP, and ATF4. However, pharmacological inhibition of ER stress prevented the butylparaben-induced induction of apoptosis. Taken together, our findings suggest that butylparaben exposure activates the ER stress-mediated apoptosis of primary cortical neurons, which is closely linked with neurodegeneration in the brain. Therefore, targeting ER stress may be considered a strategy for the treatment of butylparaben-induced neurodegeneration.

MACF1, Involved in the 1p34.2p34.3 Microdeletion Syndrome, is Essential in Cortical Progenitor Polarity and Brain Integrity.

1p34.2p34.3 deletion syndrome is characterized by an increased risk for autism. Microtubule Actin Crosslinking Factor 1 (MACF1) is one candidate gene for this syndrome. It is unclear, however, how MACF1 deletion is linked to brain development and neurodevelopmental deficits. Here we report on Macf1 deletion in the developing mouse cerebral cortex, focusing on radial glia polarity and morphological integrity, as these are critical factors in brain formation. We found that deleting Macf1 during cortical development resulted in double cortex/subcortical band heterotopia as well as disrupted cortical lamination. Macf1-deleted radial progenitors showed increased proliferation rates compared to control cells but failed to remain confined within their defined proliferation zone in the developing brain. The overproliferation of Macf1-deleted radial progenitors was associated with elevated cell cycle speed and re-entry. Microtubule stability and actin polymerization along the apical ventricular area were decreased in the Macf1 mutant cortex. Correspondingly, there was a disconnection between radial glial fibers and the apical and pial surfaces. Finally, we observed that Macf1-mutant mice exhibited social deficits and aberrant emotional behaviors. Together, these results suggest that MACF1 plays a critical role in cortical progenitor proliferation and localization by promoting glial fiber stabilization and polarization. Our findings may provide insights into the pathogenic mechanism underlying the 1p34.2p34.3 deletion syndrome.

Neurobiology of ARID1B haploinsufficiency related to neurodevelopmental and psychiatric disorders.

ARID1B haploinsufficiency is a frequent cause of intellectual disability (ID) and autism spectrum disorder (ASD), and also leads to emotional disturbances. In this review, we examine past and present clinical and preclinical research into the neurobiological function of ARID1B. The presentation of ARID1B-related disorders (ARID1B-RD) is highly heterogeneous, including varying degrees of ID, ASD, and physical features. Recent research includes the development of suitable clinical readiness assessments for the treatment of ARID1B-RD, as well as similar neurodevelopmental disorders. Recently developed mouse models of Arid1b haploinsufficiency successfully mirror many of the behavioral phenotypes of ASD and ID. These animal models have helped to solidify the molecular mechanisms by which ARID1B regulates brain development and function, including epigenetic regulation of the Pvalb gene and promotion of Wnt/ß-catenin signaling in neural progenitors in the ventral telencephalon. Finally, preclinical studies have identified the use of a positive allosteric modulator of the GABAA receptor as an effective treatment for some Arid1b haploinsufficiency-related behavioral phenotypes, and there is potential for the refinement of this therapy in order to translate it into clinical use.

Cardiac toxicity from bisphenol A exposure in human-induced pluripotent stem cell-derived cardiomyocytes.

Bisphenol A (BPA) is a well-known endocrine-disrupting chemical that is widely used in a variety of products, including plastics, medical equipment and receipts. Hence, most people are exposed to BPA through the skin, via inhalation and via the digestive system, and such exposure has been linked to cardiovascular diseases including coronary artery disease, hypertension, atherosclerosis, and myocardial infarction. However, the underlying mechanisms of cardiac dysfunction caused by BPA remain poorly understood. In this study, we found that BPA exposure altered cardiac function in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Acute BPA exposure in hiPSC-CMs resulted in reduced field potential, as measured by multielectrode array (MEA). Furthermore, we observed that BPA dose-dependently inhibited ICa, INa or IKr channels. In addition, BPA exposure dose-dependently inhibited calcium transients and contraction in hiPSC-CMs. Our findings suggest that BPA exposure leads to cardiac dysfunction and cardiac risk factors such as arrhythmia.

Maternal Bisphenol A (BPA) Exposure Alters Cerebral Cortical Morphogenesis and Synaptic Function in Mice.

Early-life exposure to bisphenol A (BPA), synthetic compound used in polycarbonate plastic, is associated with altered cognitive and emotional behavior later in life. However, the brain mechanism underlying the behavioral deficits is unknown. Here, we show that maternal BPA exposure disrupted self-renewal and differentiation of neural progenitors during cortical development. The BPA exposure reduced the neuron number, whereas it increased glial cells in the cerebral cortex. Also, synaptic formation and transmission in the cerebral cortex were suppressed after maternal BPA exposure. These changes appeared to be associated with autophagy as a gene ontology analysis of RNA-seq identified an autophagy domain in the BPA condition. Mouse behavioral tests revealed that maternal BPA caused hyperactivity and social deficits in adult offspring. Together, these results suggest that maternal BPA exposure leads to abnormal cortical architecture and function likely by activating autophagy.

Differential roles of ARID1B in excitatory and inhibitory neural progenitors in the developing cortex.

Genetic evidence indicates that haploinsufficiency of ARID1B causes intellectual disability (ID) and autism spectrum disorder (ASD), but the neural function of ARID1B is largely unknown. Using both conditional and global Arid1b knockout mouse strains, we examined the role of ARID1B in neural progenitors. We detected an overall decrease in the proliferation of cortical and ventral neural progenitors following homozygous deletion of Arid1b, as well as altered cell cycle regulation and increased cell death. Each of these phenotypes was more pronounced in ventral neural progenitors. Furthermore, we observed decreased nuclear localization of ß-catenin in Arid1b-deficient neurons. Conditional homozygous deletion of Arid1b in ventral neural progenitors led to pronounced ID- and ASD-like behaviors in mice, whereas the deletion in cortical neural progenitors resulted in minor cognitive deficits. This study suggests an essential role for ARID1B in forebrain neurogenesis and clarifies its more pronounced role in inhibitory neural progenitors. Our findings also provide insights into the pathogenesis of ID and ASD.

2-Phenylethylamine (PEA) Ameliorates Corticosterone-Induced Depression-Like Phenotype via the BDNF/TrkB/CREB Signaling Pathway.

Depression is a serious medical illness that is one of the most prevalent psychiatric disorders. Corticosterone (CORT) increases depression-like behavior, with some effects on anxiety-like behavior. 2-Phenethylamine (PEA) is a monoamine alkaloid that acts as a central nervous system stimulant in humans. Here, we show that PEA exerts antidepressant effects by modulating the Brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB)/cAMP response element binding protein (CREB) signaling pathway in CORT-induced depression. To investigate the potential effects of PEA on CORT-induced depression, we first treated CORT (50 µM)-induced hippocampal neurons with 100 µM PEA for 24 h. We found that treatment with CORT altered dendritic spine architecture; however, treatment with PEA rescued dendritic spine formation via regulation of BDNF/TrkB/CREB signaling. Next, we used a mouse model of CORT-induced depression. Mice were treated with CORT (20 mg/kg) for 21 days, followed by assessments of a battery of depression-like behaviors. During the final four days of CORT exposure, the mice were treated with PEA (50 mg/kg). We found that CORT injection promoted depression-like behavior and significantly decreased BDNF and TrkB expression in the hippocampus. However, treatment with PEA significantly ameliorated the behavioral and biochemical changes induced by CORT. Our findings reveal that PEA exerts antidepressant effects by modulating the BDNF/TrkB/CREB signaling pathway in a mouse model of CORT-induced depression.

Asparagus cochinchinensis extract ameliorates menopausal depression in ovariectomized rats under chronic unpredictable mild stress.

BACKGROUND: Depression is a serious and common psychiatric disorder generally affecting more women than men. A woman's risk of developing depression increases steadily with age, and higher incidence is associated with the onset of menopause. Here we evaluated the antidepressant properties of Asparagus cochinchinensis (AC) extract and investigated its underlying mechanisms in a rat menopausal depression model. METHODS: To model this menopausal depression, we induced a menopause-like state in rats via ovariectomy and exposed them to chronic unpredictable mild stress (CUMS) for 6 weeks, which promotes the development of depression-like symptoms. During the final 4 weeks of CUMS, rats were treated with either AC extract (1000 or 2000 mg/kg, PO), which has been reported to provide antidepressant effects, or with the tricyclic antidepressant imipramine (10 mg/kg, IP). RESULTS: We report that CUMS promotes depression-like behavior and significantly increases serum corticosterone and inflammatory cytokine levels in the serum of ovariectomized (OVX) rats. We also found that CUMS decreases the expression of brain-derived neurotrophic factor (BDNF) and its primary receptor, tropomyosin receptor kinase B (TrkB), in OVX rats, and treatment with AC extract rescues both BDNF and TrkB expression levels. CONCLUSION: These results suggest that AC extract exerts antidepressant effects, possibly via modulation of the BDNF-TrkB pathway, in a rat model of menopausal depression.

Mitigating Effects of Liriope platyphylla on Nicotine-Induced Behavioral Sensitization and Quality Control of Compounds.

In this study we investigated the mitigating effects of Liriope platyphylla Wang et Tang extract on behavioral sensitization and the quantification of its major compounds. The extract of L. platyphylla reduces the expression of tyrosine hydroxylase (TH) protein, which is increased by nicotine, back to normal levels, and increases the expression of dopamine transporter (DAT) protein, which is reduced by nicotine, back to normal levels in PC12 cells. In this study, rats received nicotine (0.4 mg/kg, subcutaneously) only for seven days and then received extract of L. platyphylla (200 or 400 mg/kg, oral) 1 h prior to nicotine administration for an additional seven days. The extract of L. platyphylla reduced locomotor activity compared to the nicotine control group in rats. The extract of L. platyphylla significantly attenuated the repeated nicotine-induced DAT protein expression in the nucleus accumbens (NAc), but there was no effect on increased TH protein expression in the dorsal striatum. These findings suggest that L. platyphylla extract has a mitigating effect on nicotine-induced behavioral sensitization by modulating DAT protein expression in the NAc. For quality control of L. plathyphylla, spicatoside A and D, which are saponin compounds, were quantified in the L. platyphylla extract. The amounts of spicatoside A and D in L. platyphylla extract obtained from ultra-high-performance liquid chromatography with tandem mass spectrometry were 0.148 and 0.272 mg/g, respectively. The identification of these compounds in L. platyphylla, which can be used for quality control, provides important information for the development of drugs to treat nicotine dependence.

The potent psychomotor, rewarding and reinforcing properties of 3-fluoromethamphetamine in rodents.

3-fluoromethamphetamine (3-FMA), a derivative of methamphetamine (METH), produces behavioral impairment and deficits in dopaminergic transmission in the striatum of mice. The abuse potential of 3-FMA has not been fully characterized. The aim of this study was to evaluate the effects of 3-FMA on locomotor activity as well as its rewarding and reinforcing properties in the conditioned place preference (CPP) and self-administration procedures. Intravenous (i.v.) administration of 3-FMA (0.5 and 1.0 mg/kg) significantly increased locomotor activity in a dose-dependent manner in rats. In the CPP procedure, intraperitoneal administration of 3-FMA (10 and 30 mg/kg) produced a significant alteration in place preference in mice. In the self-administration paradigms, 3-FMA showed drug-taking behavior at the dose of 0.1 mg/kg/infusion (i.v.) during 2 hr sessions under fixed ratio schedules and high breakpoints at the dose of 0.3 and 1.0 mg/kg/infusion (i.v.) during 6 hr sessions under progressive ratio schedule of reinforcement in rats. A priming injection of 3-FMA (0.4 mg/kg, i.v.), METH (0.2 mg/kg, i.v.), or cocaine (2.0 mg/kg, i.v.) reinstated 3-FMA-seeking behavior after an extinction period in 3-FMA-trained rats during 2 hr session. Taken together, these findings demonstrate robust psychomotor, rewarding and reinforcing properties of 3-FMA, which may underlie its potential for compulsive use in humans.

The role of ARID1B, a BAF chromatin remodeling complex subunit, in neural development and behavior.

Haploinsufficiency of the chromatin remodeling factor ARID1B leads to autism spectrum disorder and intellectual disability. Several independent research groups, including our own, recently examined the effects of heterozygous deletion of Arid1b in mice and reported severe behavioral abnormalities reminiscent of autism spectrum disorders and intellectual disability as well as marked changes in gene expression and decreased body size. Arid1b heterozygous mice also display significant cortical excitatory/inhibitory imbalance due to altered GABAergic neuron numbers and impaired inhibitory synaptic transmission. Abnormal epigenetic modifications, including histone acetylation and methylation, are additionally associated with Arid1b haploinsufficiency in the brain. Treating adult Arid1b mutant mice with a positive GABA allosteric modulator, however, rescues multiple behavioral abnormalities, such as cognitive and social impairments, as well as elevated anxiety. While treating Arid1b haploinsufficient mice with recombinant mouse growth hormone successfully increases body size, it has no effect on aberrant behavior. Here we summarize the recent findings regarding the role of ARID1B in brain development and behavior and discuss the utility of the Arid1b heterozygous mouse model in neurodevelopmental and psychiatric research. We also discuss some of the opportunities and potential challenges in developing translational applications for humans and possible avenues for further research into the mechanisms of ARID1B pathology in the brain.

Astrocyte EV-Induced lincRNA-Cox2 Regulates Microglial Phagocytosis: Implications for Morphine-Mediated Neurodegeneration.

Impairment of microglial functions, such as phagocytosis and/or dysregulation of immune responses, has been implicated as an underlying factor involved in the pathogenesis of various neurodegenerative disorders. Our previous studies have demonstrated that long intergenic noncoding RNA (lincRNA)-Cox2 expression is influenced by nuclear factor κB (NF-κB) signaling and serves as a coactivator of transcriptional factors to regulate the expression of a vast array of immune-related genes in microglia. Extracellular vesicles (EVs) have been recognized as primary facilitators of cell-to-cell communication and cellular regulation. Herein, we show that EVs derived from astrocytes exposed to morphine can be taken up by microglial endosomes, leading, in turn, to activation of Toll-like receptor 7 (TLR7) with a subsequent upregulation of lincRNA-Cox2 expression, ultimately resulting in impaired microglial phagocytosis. This was further validated in vivo, wherein inhibition of microglial phagocytic activity was also observed in brain slices isolated from morphine-administrated mice compared with control mice. Additionally, we also showed that intranasal delivery of EVs containing lincRNA-Cox2 siRNA (small interfering RNA) was able to restore microglial phagocytic activity in mice administered morphine. These findings have ramifications for the development of EV-loaded RNA-based therapeutics for the treatment of various disorders involving functional impairment of microglia.

ANKRD11 associated with intellectual disability and autism regulates dendrite differentiation via the BDNF/TrkB signaling pathway.

Haploinsufficiency of ANKRD11 due to deletion or truncation mutations causes KBG syndrome, a rare genetic disorder characterized by intellectual disability, autism spectrum disorder, and craniofacial abnormalities. However, little is known about the neurobiological role of ANKRD11 during brain development. Here we show that ANKRD11 regulates pyramidal neuron migration and dendritic differentiation in the developing mouse cerebral cortex. Using an in utero manipulation approach, we found that Ankrd11 knockdown delayed radial migration of cortical neurons. ANKRD11-deficient neurons displayed markedly reduced dendrite growth and branching as well as abnormal dendritic spine morphology. Ankrd11 knockdown suppressed acetylation of epigenetic molecules such as p53 and Histone H3. Furthermore, the mRNA levels of Trkb, Bdnf, and neurite growth-related genes were downregulated in ANKRD11-deficient cortical neurons. The Trkb promoter region was largely devoid of acetylated Histone H3 and p53, and was instead occupied with MeCP2 and DNMT1. Overexpression of TrkB rescued abnormal dendrite growth in these cells. Our findings demonstrate a novel role for ANKRD11 in neuron differentiation during brain development and suggest an epigenetic modification as a potential key molecular feature underlying KBG syndrome.

The role of MACF1 in nervous system development and maintenance.

Microtubule-actin crosslinking factor 1 (MACF1), also known as actin crosslinking factor 7 (ACF7), is essential for proper modulation of actin and microtubule cytoskeletal networks. Most MACF1 isoforms are expressed broadly in the body, but some are exclusively found in the nervous system. Consequentially, MACF1 is integrally involved in multiple neural processes during development and in adulthood, including neurite outgrowth and neuronal migration. Furthermore, MACF1 participates in several signaling pathways, including the Wnt/ß-catenin and GSK-3 signaling pathways, which regulate key cellular processes, such as proliferation and cell migration. Genetic mutation or dysregulation of the MACF1 gene has been associated with neurodevelopmental and neurodegenerative diseases, specifically schizophrenia and Parkinson's disease. MACF1 may also play a part in neuromuscular disorders and have a neuroprotective role in the optic nerve. In this review, the authors seek to synthesize recent findings relating to the roles of MACF1 within the nervous system and explore potential novel functions of MACF1 not yet examined.