Astrocytes, oligodendrocytes, and microglia are abundant cell types found in the central nervous system and have been shown to play crucial roles in regulating both normal and disease states. An increasing amount of evidence points to the critical importance of glia in mediating neurodegeneration in Alzheimer’s and Parkinson’s diseases (AD, PD), and in ischemic stroke, where microglia are involved in initial tissue clearance, and astrocytes in the subsequent formation of a glial scar. The importance of these cells for neuronal survival has previously been studied in co-culture experiments and the search for neurotrophic factors (NTFs) initiated after finding that the addition of conditioned media from astrocyte cultures could support the survival of primary neurons in vitro. This led to the discovery of the potent dopamine neurotrophic factor, glial cell line-derived neurotrophic factor (GDNF). In this review, we focus on the relationship between glia and NTFs including neurotrophins, GDNF-family ligands, CNTF family, and CDNF/MANF-family proteins. We describe their expression in astrocytes, oligodendrocytes and their precursors (NG2-positive cells, OPCs), and microglia during development and in the adult brain. Furthermore, we review existing data on the glial phenotypes of NTF knockout mice and follow NTF expression patterns and their effects on glia in disease models such as AD, PD, stroke, and retinal degeneration.

Although fatty acids support mitochondrial ATP production in most tissues, neurons are believed to rely exclusively on glucose for energy. Here we show that genetic ablation of the triglyceride and phospholipid lipase Ddhd2 impairs mitochondrial respiration and ATP synthesis in cultured neurons, despite increased glycolysis. This defect arises from reduced levels of long-chain saturated free fatty acids, particularly myristic, palmitic and stearic acids, normally released in an activity-dependent manner by Ddhd2. Inhibition of mitochondrial fatty acid import in wild-type neurons similarly reduced mitochondrial respiration and ATP production. Saturated fatty acyl-coenzyme A treatment restored mitochondrial energy production in Ddhd2 knockout neurons. When provided in combination, these activated fatty acyl-CoA supplements also rescued defects in membrane trafficking, synaptic function and protein homeostasis. These findings uncover that neurons perform β-oxidation of endogenous long-chain free fatty acids to meet ATP demands and reveal a potential therapeutic strategy for hereditary spastic paraplegia 54 caused by DDHD2 mutations.

Background: Parkinson’s disease (PD) is a motor disorder characterized by the degeneration of dopaminergic neurons, putatively due to the accumulation of α-synuclein (α-syn) in Lewy bodies (LBs) in Substantia Nigra. PD is also associated with the formation of LBs in brain areas responsible for emotional and cognitive regulation such as the amygdala and prefrontal cortex, and concurrent depression prevalence in PD patients. The exact link between dopaminergic cell loss, α-syn aggregation, depression, and stress, a major depression risk factor, is unclear. Therefore, we aimed to explore the interplay between sensitivity to chronic stress and α-syn aggregation. Methods: Bilateral injections of α-syn preformed fibrils (PFFs) into the striatum of C57Bl/6 J mice were used to induce α-syn aggregation. Three months after injections, animals were exposed to chronic social defeat stress. Results: α-syn aggregation did not affect stress susceptibility but independently caused increased locomotor activity in the open field test, reduced anxiety in the light–dark box test, and increased active time in the tail suspension test. Ex vivo analysis revealed modest dopaminergic neuron loss in the substantia nigra and reduced dopaminergic innervation in the dorsal striatum in PFFs injected groups. α-Syn aggregates were prominent in the amygdala, prefrontal cortex, and substantia nigra, with minimal α-syn aggregation in the raphe nuclei and locus coeruleus. Conclusions: Progressive bilateral α-syn aggregation might lead to compensatory activity increase and alterations in emotionally regulated behavior, without affecting stress susceptibility. Understanding how α-syn aggregation and degeneration in specific brain structures contribute to depression and anxiety in PD patients requires further investigation.

Parkinson's disease (PD) is the second most prevalent age-related neurodegenerative disorder, clinically characterized by both motor and non-motor symptoms. A key hallmark of PD is the accumulation of misfolded α-synuclein, which aggregates to Lewy bodies (LB) formed inside neurons. Trehalose, a disaccharide that induces autophagy, has been demonstrated to reduce α-synuclein aggregation in vivo. However, the enzyme trehalase rapidly degrades free trehalose, and its hydrophilicity causes poor penetration through the cell membrane. Thus, advanced trehalose delivery strategies are urgently needed. Herein, we investigated the effects of trehalose-bearing nanogels for reducing α-synuclein protein-induced perinuclear LB-like pathology in primary mouse hippocampal neurons. The study compares the effects of trehalose-releasing nanogel (TR) and trehalose-non releasing nanogel (TNR). The results showed that TR, but not TNR, nor free trehalose reduced LB-like inclusions in primary hippocampal neurons. The neuroprotective effects of TR may result from the synergistic effects of direct limitation of α-synuclein aggregates formation and trehalose release-induced autophagy promoting aggregates clearance. Overall, enhancing trehalose delivery with nanogels that can sustainably release trehalose could be worth further investigation as a new potential option for reducing α-synuclein aggregation in neurons affected by neurodegenerative diseases.

Neurodegenerative diseases are associated with proteostasis disturbances and accumulation of fibrillar proteins into insoluble aggregates. Progressive age-related degeneration of dopamine neurons is a primary cause of motor dysfunctions in Parkinson’s disease (PD) and substantial evidence supports critical involvement of α-synuclein (α-syn) in the etiology of PD. α-syn is a cytosolic protein present in high concentrations in pre-synaptic neuronal terminals and a primary constituent of intracellular protein aggregates known as Lewy Neurites or Lewy Bodies. Progression of Lewy pathology is a characteristic feature in the PD brains caused by the prion-like self-templating properties of misfolded α-syn. Modelling Lewy pathology progression with application of exogenously prepared α-syn preformed fibrils, we discovered that glial cell line-derived neurotrophic factor (GDNF) prevented formation of α-syn aggregates in dopamine neurons in culture and in vivo after viral vector expression of GDNF. These effects were abolished by CRISPR/Cas9-mediated deletion of receptor tyrosine kinase Ret , the major GDNF signaling pathway. Similar to GDNF, expression of mutated constitutively active RET (RET_MEN2B) was able to protect dopamine neurons. GDNF protection against α-syn pathology progression was abolished by Src and attenuated by Akt pathway inhibitors. For the first time, we have shown the neurotrophic factor-mediated protection against the misfolded α-syn propagation in dopamine neurons, uncovered underlying receptor and intracellular signaling pathways. These results for the first time demonstrate that activation of GDNF/RET signaling can be an effective therapeutic approach to prevent Lewy pathology spread at early stages of PD.