Patrick Aebischer

Astrocyte-targeting RNA interference against mutated superoxide dismutase 1 induces motoneuron plasticity and protects fast-fatigable motor units in a mouse model of amyotrophic lateral sclerosis

Patrick Aebischer, Nathalie Marie Géraldine Bernard, Cylia Cloé Rochat, Bernard Schneider

In amyotrophic lateral sclerosis (ALS) caused by SOD1 gene mutations, both cell-autonomous and noncell-autonomous mechanisms lead to the selective degeneration of motoneurons (MN). Here, we evaluate the therapeutic potential of gene therapy targeting mutated SOD1 in mature astrocytes using mice expressing the mutated SOD1(G93A) protein. An AAV-gfaABC(1)D vector encoding an artificial microRNA is used to deliver RNA interference against mutated SOD1 selectively in astrocytes. The treatment leads to the progressive rescue of neuromuscular junction occupancy, to the recovery of the compound muscle action potential in the gastrocnemius muscle, and significantly improves neuromuscular function. In the spinal cord, gene therapy targeting astrocytes protects a small pool of the most vulnerable fast-fatigable MN until disease end stage. In the gastrocnemius muscle of the treated SOD1(G93A) mice, the fast-twitch type IIB muscle fibers are preserved from atrophy. Axon collateral sprouting is observed together with muscle fiber type grouping indicative of denervation/reinnervation events. The transcriptome profiling of spinal cord MN shows changes in the expression levels of factors regulating the dynamics of microtubules. Gene therapy delivering RNA interference against mutated SOD1 in astrocytes protects fast-fatigable motor units and thereby improves neuromuscular function in ALS mice.

WILEY2022

Evolution of the neurochemical profiles in the G93A-SOD1 mouse model of amyotrophic lateral sclerosis

Patrick Aebischer, Elisabeth Anne Dirren, Rolf Gruetter, Hongxia Lei, Carole Poitry-Yamate, Bernard Schneider

In vivo (1)H magnetic resonance spectroscopy ((1)H-MRS) investigations of amyotrophic lateral sclerosis (ALS) mouse brain may provide neurochemical profiles and alterations in association with ALS disease progression. We aimed to longitudinally follow neurochemical evolutions of striatum, brainstem and motor cortex of mice transgenic for G93A mutant human superoxide dismutase type-1 (G93A-SOD1), an ALS model. Region-specific neurochemical alterations were detected in asymptomatic G93A-SOD1 mice, particularly in lactate (-19%) and glutamate (+8%) of brainstem, along with gamma-amino-butyric acid (-30%), N-acetyl-aspartate (-5%) and ascorbate (+51%) of motor cortex. With disease progression towards the end-stage, increased numbers of metabolic changes of G93A-SOD1 mice were observed (e.g. glutamine levels increased in the brainstem (>+66%) and motor cortex (>+54%)). Through ALS disease progression, an overall increase of glutamine/glutamate in G93A-SOD1 mice was observed in the striatum ( p < 0.01) and even more so in two motor neuron enriched regions, the brainstem and motor cortex ( p < 0.0001). These (1)H-MRS data underscore a pattern of neurochemical alterations that are specific to brain regions and to disease stages of the G93A-SOD1 mouse model. These neurochemical changes may contribute to early diagnosis and disease monitoring in ALS patients.

2019

The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans

Patrick Aebischer, Pénélope Andreux, Johan Auwerx, Frederic Burdet, Dongryeol Ryu, Anurag Singh

Urolithin A (UA) is a natural dietary, microflora-derived metabolite shown to stimulate mitophagy and improve muscle health in old animals and in preclinical models of aging(1). Here, we report the results of a first-in-human clinical trial in which we administered UA, either as a single dose or as multiple doses over a 4-week period, to healthy, sedentary elderly individuals. We show that UA has a favourable safety profile (primary outcome). UA was bioavailable in plasma at all doses tested, and 4 weeks of treatment with UA at doses of 500 mg and 1,000 mg modulated plasma acylcarnitines and skeletal muscle mitochondrial gene expression in elderly individuals (secondary outcomes). These observed effects on mitochondrial biomarkers show that UA induces a molecular signature of improved mitochondrial and cellular health following regular oral consumption in humans.

NATURE PUBLISHING GROUP2019

Parkin functionally interacts with PGC-1 proportional to to preserve mitochondria and protect dopaminergic neurons

Patrick Aebischer, Johan Auwerx, Nathalie Marie Géraldine Bernard, Graham Knott, Darren Moore, Norman Lionel Moullan, Bernard Schneider, Lu Zheng

To understand the cause of Parkinson's disease (PD), it is important to determine the functional interactions between factors linked to the disease. Parkin is associated with autosomal recessive early-onset PD, and controls the transcription of PGC-1a, a master regulator of mitochondrial biogenesis. These two factors functionally interact to regulate the turnover and quality of mitochondria, by increasing both mitophagic activity and mitochondria biogenesis. In cortical neurons, co- expressing PGC-1a and Parkin increases the number of mitochondria, enhances maximal respiration, and accelerates the recovery of the mitochondrial membrane potential following mitochondrial uncoupling. PGC-1a enhances Mfn2 transcription, but also leads to increased degradation of the Mfn2 protein, a key ubiquitylation target of Parkin on mitochondria. In vivo, Parkin has significant protective effects on the survival and function of nigral dopaminergic neurons in which the chronic expression of PGC1a is induced. Ultrastructural analysis shows that these two factors together control the density of mitochondria and their interaction with the endoplasmic reticulum. These results highlight the combined effects of Parkin and PGC- 1a in the maintenance of mitochondrial homeostasis in dopaminergic neurons. These two factors synergistically control the quality and function of mitochondria, which is important for the survival of neurons in Parkinson's disease.

Oxford Univ Press2017

A subcutaneous cellular implant for passive immunization against amyloid-beta reduces brain amyloid and tau pathologies

Patrick Aebischer, Aurélien Lathuilière, Vanessa Laversenne, Bernard Schneider, Marco Stampanoni

Passive immunization against toxic misfolded proteins could offer protection against neurodegenerative disease. LathuiliSre et al. report the development of a retrievable device to encapsulate cells secreting recombinant anti-amyloid-beta antibodies. When implanted in mouse models of Alzheimer's disease, the system delivers antibodies to the brain and reduces amyloid and tau pathologies.Passive immunization against toxic misfolded proteins could offer protection against neurodegenerative disease. LathuiliSre et al. report the development of a retrievable device to encapsulate cells secreting recombinant anti-amyloid-beta antibodies. When implanted in mouse models of Alzheimer's disease, the system delivers antibodies to the brain and reduces amyloid and tau pathologies.Passive immunization against misfolded toxic proteins is a promising approach to treat neurodegenerative disorders. For effective immunotherapy against Alzheimer's disease, recent clinical data indicate that monoclonal antibodies directed against the amyloid-beta peptide should be administered before the onset of symptoms associated with irreversible brain damage. It is therefore critical to develop technologies for continuous antibody delivery applicable to disease prevention. Here, we addressed this question using a bioactive cellular implant to deliver recombinant anti-amyloid-beta antibodies in the subcutaneous tissue. An encapsulating device permeable to macromolecules supports the long-term survival of myogenic cells over more than 10 months in immunocompetent allogeneic recipients. The encapsulated cells are genetically engineered to secrete high levels of anti-amyloid-beta antibodies. Peripheral implantation leads to continuous antibody delivery to reach plasma levels that exceed 50 A mu g/ml. In a proof-of-concept study, we show that the recombinant antibodies produced by this system penetrate the brain and bind amyloid plaques in two mouse models of the Alzheimer's pathology. When encapsulated cells are implanted before the onset of amyloid plaque deposition in TauPS2APP mice, chronic exposure to anti-amyloid-beta antibodies dramatically reduces amyloid-beta(40) and amyloid-beta(42) levels in the brain, decreases amyloid plaque burden, and most notably, prevents phospho-tau pathology in the hippocampus. These results support the use of encapsulated cell implants for passive immunotherapy against the misfolded proteins, which accumulate in Alzheimer's disease and other neurodegenerative disorders.

Oxford Univ Press2016

In Vivo Evidence for a Lactate Gradient from Astrocytes to Neurons

Patrick Aebischer, Maha Elsayed, Sylvain Eric Lengacher, Pierre Magistretti, Bernard Schneider

Investigating lactate dynamics in brain tissue is challenging, partly because in vivo data at cellular resolution are not available. We monitored lactate in cortical astrocytes and neurons of mice using the genetically encoded FRET sensor Laconic in combination with two-photon microscopy. An intravenous lactate injection rapidly increased the Laconic signal in both astrocytes and neurons, demonstrating high lactate permeability across tissue. The signal increase was significantly smaller in astrocytes, pointing to higher basal lactate levels in these cells, confirmed by a one-point calibration protocol. Trans-acceleration of the monocarboxylate transporter with pyruvate was able to reduce intracellular lactate in astrocytes but not in neurons. Collectively, these data provide in vivo evidence for a lactate gradient from astrocytes to neurons. This gradient is a prerequisite for a carrier-mediated lactate flux from astrocytes to neurons and thus supports the astrocyte-neuron lactate shuttle model, in which astrocyte-derived lactate acts as an energy substrate for neurons.

Cell Press2016

Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents

Patrick Aebischer, Pénélope Andreux, Johan Auwerx, Damien Sébastien Huzard, Pooja Jha, Elena Katsyuba, Giuseppe Lo Sasso, Laurent Mouchiroud, Norman Lionel Moullan, Dongryeol Ryu, Maria del Carmen Sandi Perez, Evan Graehl Williams

The biological effects of urolithins remain poorly characterized, despite wide-spread human exposure via the dietary consumption of their metabolic precursors, the ellagitannins, which are found in the pomegranate fruit, as well as in nuts and berries. We identified urolithin A (UA) as a first-in-class natural compound that induces mitophagy both in vitro and in vivo following oral consumption. In C. elegans, UA prevented the accumulation of dysfunctional mitochondria with age and extended lifespan. Likewise, UA prolonged normal activity during aging in C. elegans, including mobility and pharyngeal pumping, while maintaining mitochondrial respiratory capacity. These effects translated to rodents, where UA improved exercise capacity in two different mouse models of age-related decline of muscle function, as well as in young rats. Our findings highlight the health benefits of urolithin A and its potential application in strategies to improve mitochondrial and muscle function.

Nature Publishing Group2016

Patrick Aebischer

Astrocyte-targeting RNA interference against mutated superoxide dismutase 1 induces motoneuron plasticity and protects fast-fatigable motor units in a mouse model of amyotrophic lateral sclerosis

Evolution of the neurochemical profiles in the G93A-SOD1 mouse model of amyotrophic lateral sclerosis

The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans

Cas9/gRNA selective targeting of the Beethoven tmc-1 mutant allele for treating progressive hearing loss by AAV-based delivery

Cas9/gRNAs Selective Targeting of the Beethoven Tmc-1 Mutant Allele for Treating Progressive Hearing Loss by AAV-Based Delivery

Cas9/gRNAs Selective Targeting of the Beethoven Tmc-1 Mutant Allele for Treating Progressive Hearing Loss by AAV-Based Delivery

Parkin functionally interacts with PGC-1 proportional to to preserve mitochondria and protect dopaminergic neurons

A subcutaneous cellular implant for passive immunization against amyloid-beta reduces brain amyloid and tau pathologies

In Vivo Evidence for a Lactate Gradient from Astrocytes to Neurons

Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents

Cas9/gRNA selective targeting of the Beethoven tmc-1 mutant allele for treating progressive hearing loss by AAV-based delivery

The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans

Cas9/gRNAs Selective Targeting of the Beethoven Tmc-1 Mutant Allele for Treating Progressive Hearing Loss by AAV-Based Delivery

Evolution of the neurochemical profiles in the G93A-SOD1 mouse model of amyotrophic lateral sclerosis

Astrocyte-targeting RNA interference against mutated superoxide dismutase 1 induces motoneuron plasticity and protects fast-fatigable motor units in a mouse model of amyotrophic lateral sclerosis

Cas9/gRNAs Selective Targeting of the Beethoven Tmc-1 Mutant Allele for Treating Progressive Hearing Loss by AAV-Based Delivery

In Vivo Evidence for a Lactate Gradient from Astrocytes to Neurons

Parkin functionally interacts with PGC-1 proportional to to preserve mitochondria and protect dopaminergic neurons

A subcutaneous cellular implant for passive immunization against amyloid-beta reduces brain amyloid and tau pathologies

Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents