Glial cells are functionally impaired in juvenile neuronal ceroid lipofuscinosis and detrimental to neurons

Abstract

The neuronal ceroid lipofuscinoses (NCLs or Batten disease) are a group of inherited, fatal neurodegenerative disorders of childhood. In these disorders, glial (microglial and astrocyte) activation typically occurs early in disease progression and predicts where neuron loss subsequently occurs. We have found that in the most common juvenile form of NCL (CLN3 disease or JNCL) this glial response is less pronounced in both mouse models and human autopsy material, with the morphological transformation of both astrocytes and microglia severely attenuated or delayed. To investigate their properties, we isolated glia and neurons from Cln3-deficient mice and studied their basic biology in culture. Upon stimulation, both Cln3-deficient astrocytes and microglia also showed an attenuated ability to transform morphologically, and an altered protein secretion profile. These defects were more pronounced in astrocytes, including the reduced secretion of a range of neuroprotective factors, mitogens, chemokines and cytokines, in addition to impaired calcium signalling and glutamate clearance. Cln3-deficient neurons also displayed an abnormal organization of their neurites. Most importantly, using a co-culture system, Cln3-deficient astrocytes and microglia had a negative impact on the survival and morphology of both Cln3-deficient and wildtype neurons, but these effects were largely reversed by growing mutant neurons with healthy glia. These data provide evidence that CLN3 disease astrocytes are functionally compromised. Together with microglia, they may play an active role in neuron loss in this disorder and can be considered as potential targets for therapeutic interventions.Electronic supplementary materialThe online version of this article (10.1186/s40478-017-0476-y) contains supplementary material, which is available to authorized users.

Oxidative Stress, a Crossroad Between Rare Diseases and Neurodegeneration

“…Although the primary cause of PMEs is different in each case, recent reports suggest that oxidative stress and neuroinflammation are common traits in all these conditions [161][162][163]. This reinforces the idea that oxidative stress and neuroinflammation are at the crossroad of rare neurodegenerative disorders.…”

Caspase 1 activity influences juvenile Batten disease (CLN3) pathogenesis

“…Recently, Cln3 −/− astrocytes have also been shown to release less cytokines, chemokines, neurotrophic factors, and the antioxidant glutathione (Parviainen et al . ). Taken together, these findings suggest that the loss of CLN3 function in astrocytes diminishes their ability to maintain brain homeostasis and neuronal support.…”

“…Additionally, Cln3 −/− astrocytes have been shown to have impaired support for neuronal survival through reductions in growth factor production and glutamate uptake (Parviainen et al . ).…”

Modulating membrane fluidity corrects Batten disease phenotypes in vitro and in vivo

“…As CBX does not cross the BBB (Leshchenko et al, 2006; Takeuchi et al, 2011), the metabolite enoxolone may be responsible for the reduced autofluorescent storage either by improving the astrocytic phenotype, the endothelial phenotype, or both. Studies show that amyloid-β accumulation in Alzheimer’s disease brain is due in part to faulty clearance by brain endothelial cells (Sagare et al, 2013), and recent work in the JNCL field shows that, in vitro , normalizing astrocytes can improve neuronal phenotypes (Parviainen et al, 2017). Regardless of the exact cell type and mechanism of action, CBX and the LINCS compounds provide promising therapeutic avenues for treatment of CLN3 deficiency disease.…”