Activation of PPARα Exhibits Therapeutic Efficacy in a Mouse Model of Juvenile Neuronal Ceroid Lipofuscinosis

Jana, Malabendu; Dutta, Debashis; Poddar, Jit; Pahan, Kalipada

doi:10.1523/jneurosci.2447-21.2023

Cited by 11 publications

(6 citation statements)

References 71 publications

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“…Transcription factor EB (TFEB) is considered as the master regulator of lysosomal biogenesis and autophagy [ 34 , 58 ]. It has been found that the TFEB gene promoter harbors a peroxisome proliferator response element and that activation of peroxisome proliferator-activated receptor α (PPARα) stimulates the transcription of TFEB gene via PPRE [ 35 , 59 ], [ 60 ], [ 61 ]. Although the classical role of PPARα is to stimulate the biogenesis of peroxisomes [ 37 , 62 ], we have seen that PPARα is also responsible for lysosomal biogenesis [ 35 , 59 ].…”

Section: Discussionmentioning

confidence: 99%

Cinnamic acid, a natural plant compound, exhibits neuroprotection in a mouse model of Sandhoff disease via PPARα

Raha,

Paidi,

Dutta

et al. 2024

NeuroImmune Pharmacology and Therapeutics

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Tay-Sachs disease (TSD) and its severe form Sandhoff disease (SD) are autosomal recessive lysosomal storage metabolic disorders, which often result into excessive GM2 ganglioside accumulation predominantly in lysosomes of nerve cells. Although patients with these diseases appear normal at birth, the progressive accumulation of undegraded GM2 gangliosides in neurons leads to early death accompanied by manifestation of motor difficulties and gradual loss of behavioral skills. Unfortunately, there is still no effective treatment available for TSD/SD. The present study highlights the importance of cinnamic acid (CA), a naturally occurring aromatic fatty acid present in a number of plants, in inhibiting the disease process in a transgenic mouse model of SD. Oral administration of CA significantly attenuated glial activation and inflammation and reduced the accumulation of GM2 gangliosides/glycoconjugates in the cerebral cortex of Sandhoff mice. Besides, oral CA also improved behavioral performance and increased the survival of Sandhoff mice. While assessing the mechanism, we found that oral administration of CA increased the level of peroxisome proliferator-activated receptor α (PPARα) in the brain of Sandhoff mice and that oral CA remained unable to reduce glycoconjugates, improve behavior and increase survival in Sandhoff mice lacking PPARα. Our results indicate a beneficial function of CA that utilizes a PPARα-dependent mechanism to halt the progression of SD and thereby increase the longevity of Sandhoff mice.

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Section: Discussionmentioning

confidence: 99%

Cinnamic acid, a natural plant compound, exhibits neuroprotection in a mouse model of Sandhoff disease via PPARα

Raha,

Paidi,

Dutta

et al. 2024

NeuroImmune Pharmacology and Therapeutics

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“…This suggests that a lack of α-mannosidase resulted in general impairment of the autophagolysosomal system. A number of studies suggest that treatments that alter the function of the autophagolysosomal system may have therapeutic benefits in treating lysosomal storage diseases like α-mannosidosis [ 113 , 114 , 115 , 116 , 117 ].…”

Section: Discussionmentioning

confidence: 99%

A Homozygous MAN2B1 Missense Mutation in a Doberman Pinscher Dog with Neurodegeneration, Cytoplasmic Vacuoles, Autofluorescent Storage Granules, and an α-Mannosidase Deficiency

Bullock,

Johnson,

Pattridge

et al. 2023

Genes

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A 7-month-old Doberman Pinscher dog presented with progressive neurological signs and brain atrophy suggestive of a hereditary neurodegenerative disorder. The dog was euthanized due to the progression of disease signs. Microscopic examination of tissues collected at the time of euthanasia revealed massive accumulations of vacuolar inclusions in cells throughout the central nervous system, suggestive of a lysosomal storage disorder. A whole genome sequence generated with DNA from the affected dog contained a likely causal, homozygous missense variant in MAN2B1 that predicted an Asp104Gly amino acid substitution that was unique among whole genome sequences from over 4000 dogs. A lack of detectable α-mannosidase enzyme activity confirmed a diagnosis of a-mannosidosis. In addition to the vacuolar inclusions characteristic of α-mannosidosis, the dog exhibited accumulations of autofluorescent intracellular inclusions in some of the same tissues. The autofluorescence was similar to that which occurs in a group of lysosomal storage disorders called neuronal ceroid lipofuscinoses (NCLs). As in many of the NCLs, some of the storage bodies immunostained strongly for mitochondrial ATP synthase subunit c protein. This protein is not a substrate for α-mannosidase, so its accumulation and the development of storage body autofluorescence were likely due to a generalized impairment of lysosomal function secondary to the accumulation of α-mannosidase substrates. Thus, it appears that storage body autofluorescence and subunit c accumulation are not unique to the NCLs. Consistent with generalized lysosomal impairment, the affected dog exhibited accumulations of intracellular inclusions with varied and complex ultrastructural features characteristic of autophagolysosomes. Impaired autophagic flux may be a general feature of this class of disorders that contributes to disease pathology and could be a target for therapeutic intervention. In addition to storage body accumulation, glial activation indicative of neuroinflammation was observed in the brain and spinal cord of the proband.

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“…Immunostaining was performed as described earlier [ 30 , 31 ]. Briefly, coverslips containing 200–300 cells/mm 2 were fixed with 4 % paraformaldehyde for 15 min, followed by treatment with cold methanol (−20 °C) for 5 min and two rinses in PBS.…”

Section: Methodsmentioning

confidence: 99%

A simple protocol for isolating microglia from adult mouse brain

Chakrabarti,

Gorai,

Pahan

2023

NeuroImmune Pharmacology and Therapeutics

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Objectives Although microglia are activated in adult and aged brains resulting in neurodegenerative and neuroinflammatory disorders, most of the cell culture studies on microglia deal with neonatal microglia because of ease of isolation. Microglia could be isolated from adult brains, but it requires separation by density gradient centrifugation, magnetic beads, etc. Here, we describe a simple protocol of isolating highly purified microglia from adult mouse brains. Methods Our protocol involves dilution with sterile PBS or media, regular centrifugation, and plating on poly-D-lysine-coated flasks. Results These adult microglia expressed the inducible nitric oxide synthase in response to preformed α-syn fibril, an etiological reagent of Parkinson’s disease, and bacterial lipopolysaccharides, one of the prototype proinflammatory stimuli. Moreover, these adult microglia exhibited phagocytosis, which was stimulated by LPS treatment. Conclusions These results suggest that adult microglia isolated by our procedure are functional and that these adult microglia could be used for studies related to neurodegenerative disorders.

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Activation of PPARα Exhibits Therapeutic Efficacy in a Mouse Model of Juvenile Neuronal Ceroid Lipofuscinosis

Cited by 11 publications

References 71 publications

Cinnamic acid, a natural plant compound, exhibits neuroprotection in a mouse model of Sandhoff disease via PPARα

Cinnamic acid, a natural plant compound, exhibits neuroprotection in a mouse model of Sandhoff disease via PPARα

A Homozygous MAN2B1 Missense Mutation in a Doberman Pinscher Dog with Neurodegeneration, Cytoplasmic Vacuoles, Autofluorescent Storage Granules, and an α-Mannosidase Deficiency

A simple protocol for isolating microglia from adult mouse brain

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