TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS.

Cytoplasmic accumulation of TDP-43 is a disease hallmark for many cases of amyotrophic lateral sclerosis (ALS), associated with a neuroinflammatory cytokine profile related to upregulation of nuclear factor κB (NF-κB) and type I interferon (IFN) pathways. Here we show that this inflammation is driven by the cytoplasmic DNA sensor cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) when TDP-43 invades mitochondria and releases DNA via the permeability transition pore. Pharmacologic inhibition or genetic deletion of cGAS and its downstream signaling partner STING prevents upregulation of NF-κB and type I IFN induced by TDP-43 in induced pluripotent stem cell (iPSC)-derived motor neurons and in TDP-43 mutant mice.

Catastrophic consequences: can the feline parasite Toxoplasma gondii prompt the purrfect neuroinflammatory storm following traumatic brain injury?

Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality worldwide; however, treatment development is hindered by the heterogenous nature of TBI presentation and pathophysiology. In particular, the degree of neuroinflammation after TBI varies between individuals and may be modified by other factors such as infection. Toxoplasma gondii, a parasite that infects approximately one-third of the world's population, has a tropism for brain tissue and can persist as a life-long infection.

Pathogenic Infection in Male Mice Changes Sperm Small RNA Profiles and Transgenerationally Alters Offspring Behavior.

Germline epigenetic factors influence transgenerational inheritance of behavioral traits upon changes in experience and environment. Immune activation due to infection can also modulate brain function, but whether this experience can be passed down to offspring remains unknown. Here, we show that infection of the male lineage with the common human parasite Toxoplasma results in transgenerational behavioral changes in offspring in a sex-dependent manner.

Impaired social behaviour and molecular mediators of associated neural circuits during chronic Toxoplasma gondii infection in female mice.

Toxoplasma gondii (T. gondii) is a neurotropic parasite that is associated with various neuropsychiatric disorders. Rodents infected with T.

Toxoplasmosis: A pathway to neuropsychiatric disorders.

Toxoplasma gondii is an obligate intracellular parasite that resides, in a latent form, in the human central nervous system. Infection with Toxoplasma drastically alters the behaviour of rodents and is associated with the incidence of specific neuropsychiatric conditions in humans. But the question remains: how does this pervasive human pathogen alter behaviour of the mammalian host? This fundamental question is receiving increasing attention as it has far reaching public health implications for a parasite that is very common in human populations.

Proteolytic Degradation of Hippocampal STEP in LTP and Learning.

Striatal-enriched protein tyrosine phosphatase (STEP) modulates key signaling molecules involved in synaptic plasticity and neuronal function. It is postulated that STEP opposes the development of long-term potentiation (LTP) and that it exerts a restraint on long-term memory (LTM). Here, we examined whether STEP levels are regulated during hippocampal LTP and after training in hippocampal-dependent tasks.

Age-related changes in STriatal-Enriched protein tyrosine Phosphatase levels: Regulation by BDNF.

Recent results indicate that STriatal-Enriched protein tyrosine Phosphatase (STEP) levels are regulated by brain-derived neurotrophic factor (BDNF), whose expression changes during postnatal development and aging. Here, we studied STEP ontogeny in mouse brain and changes in STEP with age with emphasis on the possible regulation by BDNF. We found that STEP expression increased during the first weeks of life, reaching adult levels by 2-3weeks of age in the striatum and cortex, and by postnatal day (P) 7 in the hippocampus.

Synaptopathic mechanisms of neurodegeneration and dementia: Insights from Huntington's disease.

Dementia encapsulates a set of symptoms that include loss of mental abilities such as memory, problem solving or language, and reduces a person's ability to perform daily activities. Alzheimer's disease is the most common form of dementia, however dementia can also occur in other neurological disorders such as Huntington's disease (HD). Many studies have demonstrated that loss of neuronal cell function manifests pre-symptomatically and thus is a relevant therapeutic target to alleviate symptoms.

BDNF Induces Striatal-Enriched Protein Tyrosine Phosphatase 61 Degradation Through the Proteasome.

Brain-derived neurotrophic factor (BDNF) promotes synaptic strengthening through the regulation of kinase and phosphatase activity. Conversely, striatal-enriched protein tyrosine phosphatase (STEP) opposes synaptic strengthening through inactivation or internalization of signaling molecules. Here, we investigated whether BDNF regulates STEP levels/activity.

Hyperactivation of D1 and A2A receptors contributes to cognitive dysfunction in Huntington's disease.

Stimulation of dopamine D1 receptor (D1R) and adenosine A2A receptor (A2AR) increases cAMP-dependent protein kinase (PKA) activity in the brain. In Huntington's disease, by essentially unknown mechanisms, PKA activity is increased in the hippocampus of mouse models and patients and contributes to hippocampal-dependent cognitive impairment in R6 mice. Here, we show for the first time that D1R and A2AR density and functional efficiency are increased in hippocampal nerve terminals from R6/1 mice, which accounts for increased cAMP levels and PKA signaling.

PDE10 inhibition increases GluA1 and CREB phosphorylation and improves spatial and recognition memories in a Huntington's disease mouse model.

Huntington's disease (HD) causes motor disturbances, preceded by cognitive impairment, in patients and mouse models. We showed that increased hippocampal cAMP-dependent protein kinase (PKA) signaling disrupts recognition and spatial memories in R6 HD mouse models. However, unchanged levels of hippocampal phosphorylated (p) cAMP-responsive element-binding protein (CREB) suggested unaltered nuclear PKA activity in R6 mice.

Increased 5-methylcytosine and decreased 5-hydroxymethylcytosine levels are associated with reduced striatal A2AR levels in Huntington's disease.

Adenosine A2A receptor (A2AR) is a G-protein-coupled receptor highly expressed in basal ganglia. Its expression levels are severely reduced in Huntington's disease (HD), and several pharmacological therapies have shown its implication in this neurodegenerative disorder. The main goal of this study was to gain insight into the molecular mechanisms that regulate A2AR gene (ADORA2A) expression in HD.