Maintenance of neuronal homeostasis is a challenging task, due to unique cellular organization and bioenergetic demands of post-mitotic neurons. It is increasingly appreciated that impairment of mitochondrial homeostasis represents an early sign of neuronal dysfunction that is common in both age-related neurodegenerative as well as in neurodevelopmental disorders. Mitochondrial selective autophagy, known as mitophagy, regulates mitochondrial number ensuring cellular adaptation in response to several intracellular and environmental stimuli. Mounting evidence underlines that deregulation of mitophagy levels has an instructive role in the process of neurodegeneration. Although mitophagy induction mediates the elimination of damaged mitochondria and confers neuroprotection, uncontrolled runaway mitophagy could reduce mitochondrial content overstressing the remaining organelles and eventually triggering neuronal cell death. Unveiling the molecular mechanisms of neuronal mitophagy and its intricate role in neuronal survival and cell death, will assist in the development of novel mitophagy modulators to promote cellular and organismal homeostasis in health and disease.

Guillain-Barre Syndrome (GBS), a common cause of acute flaccid paralysis, is characterized by a rapidly progressive, usually symmetric weakness of the extremities. Headache and intracranial hypertension (ICHT) are very rare complications of GBS. Herein we report our current case of an obese girl with typical signs of GBS associated with autonomic dysfunction, cranial nerve deficits and increased intracranial pressure (ICP). We also perform a systematic study presenting and discussing previous case reports of GBS associated with ICHT, papilledema or hydrocephalus, highlighting the differences of the current case compared to previous studies. Although intracranial hypertension is a rare complication of pediatric GBS, clinicians should promptly detect it. Obesity may be a predisposing factor, given the strong association between idiopathic intracranial hypertension (IIH) and weight gain. Neurological evaluation, fundus examination and low threshold for intracranial imaging should be an integral part of medical practice in case of obesity, headache or visual changes in GBS patients.

Neurodegenerative diseases are strongly age-related and currently cannot be cured, with a surge of patient numbers in the coming decades in view of the emerging worldwide ageing population, bringing healthcare and socioeconomic challenges. Effective therapies are urgently needed, and are dependent on new aetiological mechanisms. In neurons, efficient clearance of damaged mitochondria, through the highly evolutionary conserved cellular process termed mitophagy, plays a fundamental role in mitochondrial and metabolic homeostasis, energy supply, neuronal survival, and health. Conversely, defective mitophagy leads to accumulation of damaged mitochondria and cellular dysfunction, contributing to ageing and age-predisposed neurodegeneration. Here, we discuss the contribution of defective mitophagy in these diseases, and underlying molecular mechanisms, and highlight novel therapeutics based on new discovered mitophagy-inducing strategies.

Maintenance of synaptic homeostasis is a challenging task, due to the intricate spatial organization and intense activity of synapses. Typically, synapses are located far away from the neuronal cell body, where they orchestrate neuronal signalling and communication, through neurotransmitter release. Stationary mitochondria provide energy required for synaptic vesicle cycling, and preserve ionic balance by buffering intercellular calcium at synapses. Thus, synaptic homeostasis is critically dependent on proper mitochondrial function. Indeed, defective mitochondrial metabolism is a common feature of several neurodegenerative and psychiatric disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), bipolar disorders and schizophrenia among others, which are also accompanied by excessive synaptic abnormalities. Specialized and compartmentalized quality control mechanisms have evolved to restore and maintain synaptic energy metabolism. Here, we survey recent advances towards the elucidation of the pivotal role of mitochondria in neurotransmission and implicating mitophagy in the maintenance of synaptic homeostasis during ageing.

Battling human neurodegenerative pathologies and managing their pervasive socioeconomic impact is becoming a global priority. Notwithstanding their detrimental effects on the human life quality and the healthcare system, the majority of human neurodegenerative disorders still remain incurable and non-preventable. Therefore, the development of novel therapeutic interventions against such maladies is becoming a pressing urgency. Age-associated deterioration of neuronal circuits and function is evolutionarily conserved in organisms as diverse as the lowly worm Caenorhabditis elegans and humans, signifying similarities in the underlying cellular and molecular mechanisms. C. elegans is a highly malleable genetic model, which offers a well-characterized nervous system, body transparency and a diverse repertoire of genetic and imaging techniques to assess neuronal activity and quality control during ageing. Here, we introduce and describe methodologies utilizing some versatile nematode models, including hyperactivated ion channel-induced necrosis (e.g., deg-3(d) and mec-4(d)) and protein aggregate (e.g., alpha-syunclein and poly-glutamate)-induced neurotoxicity, to monitor and dissect the cellular and molecular underpinnings of age-related neuronal breakdown. A combination of these animal neurodegeneration models, together with genetic and pharmacological screens for cell death modulators will lead to an unprecedented understanding of age-related breakdown of neuronal function and will provide critical insights with broad relevance to human health and quality of life.

Maintaining a healthy proteome is essential for cell and organismal homeostasis. Perturbation of the balance between protein translational control and degradation instigates a multitude of age-related diseases. Decline of proteostasis quality control mechanisms is a hallmark of ageing. Biochemical methods to detect de novo protein synthesis are still limited, have several disadvantages and cannot be performed in live cells or animals. Caenorhabditis elegans, being transparent and easily genetically modified, is an excellent model to monitor protein synthesis rates by using imaging techniques. Here, we introduce and describe a method to measure de novo protein synthesis in vivo utilizing fluorescence recovery after photobleaching (FRAP). Transgenic animals expressing fluorescent proteins in specific cells or tissues are irradiated by a powerful light source resulting in fluorescence photobleaching. In turn, assessment of fluorescence recovery signifies new protein synthesis in cells and/or tissues of interest. Hence, the combination of transgenic nematodes, genetic and/or pharmacological interventions together with live imaging of protein synthesis rates can shed light on mechanisms mediating age-dependent proteostasis collapse.

In autosomal dominant optic atrophy (ADOA), caused by mutations in the mitochondrial cristae biogenesis and fusion protein optic atrophy 1 (Opa1), retinal ganglion cell (RGC) dysfunction and visual loss occur by unknown mechanisms. Here, we show a role for autophagy in ADOA pathogenesis. In RGCs expressing mutated Opa1, active 5' AMP-activated protein kinase (AMPK) and its autophagy effector ULK1 accumulate at axonal hillocks. This AMPK activation triggers localized hillock autophagosome accumulation and mitophagy, ultimately resulting in reduced axonal mitochondrial content that is restored by genetic inhibition of AMPK and autophagy. In C. elegans, deletion of AMPK or of key autophagy and mitophagy genes normalizes the axonal mitochondrial content that is reduced upon mitochondrial dysfunction. In conditional, RGC specific Opa1-deficient mice, depletion of the essential autophagy gene Atg7 normalizes the excess autophagy and corrects the visual defects caused by Opa1 ablation. Thus, our data identify AMPK and autophagy as targetable components of ADOA pathogenesis.