Interconnected neurons with a glowing Calmodulin molecule symbolizing regulatory role in NCL.

Batten Disease: Unlocking the Calcium Connection for Future Therapies

Kai Mendoza in Health & Wellness August 2025 • 4 min read.

"Could Calmodulin hold the key to understanding and treating Neuronal Ceroid Lipofuscinoses (NCLs)?"

Batten disease, also known as neuronal ceroid lipofuscinosis (NCL), is a devastating neurodegenerative disorder affecting individuals of all ages. It leads to vision loss, seizures, motor function decline, cognitive impairment, and a shortened lifespan. Currently, Brineura is the only clinically approved therapeutic, but it targets only one specific subtype of the disease (CLN2 disease) due to a limited understanding of NCL proteins and their functions.

Scientists have identified 13 distinct genes (CLN1–8, CLN10–14) associated with NCL, encoding various proteins with different cellular roles, including enzymes, transmembrane proteins, and cytoplasmic components. They're linked to fundamental cellular processes like sphingolipid metabolism, protein degradation, and lysosomal pH homeostasis. Mutations in these NCL proteins result in similar clinical phenotypes, suggesting their involvement in shared biological pathways.

A recent study has revealed a potential link between calcium signaling and NCL proteins, with Calmodulin (CaM) emerging as a central player. CaM regulates various cellular processes affected in NCLs, making it a promising therapeutic target.

Calmodulin (CaM): The Overlooked Link in NCL Protein Function?

Interconnected neurons with a glowing Calmodulin molecule symbolizing regulatory role in NCL.

Eukaryotic cells use calcium to regulate cellular processes, including nerve cell transmission, motility, exocytosis, apoptosis, and transcription. CaM, the primary calcium sensor in the cell, undergoes conformational changes in the presence of calcium, enabling it to bind and regulate CaM-binding proteins (CaMBPs). Proteomic screens have identified numerous calcium-dependent CaMBPs in the mammalian brain with various functions, including neuronal nitric oxide synthase, calcineurin A, calcium/CaM-dependent protein kinase II (CaMKII), calcium/CaM-dependent protein kinase kinase, and calcium channel proteins.

CaM regulates critical molecular pathways, including autophagy, apoptosis, adhesion, endocytosis, protein secretion, lipid metabolism, lysosomal dynamics, and DNA repair. Interestingly, these processes are also affected in various NCL subtypes. The existing research indicates a link between CaM and NCLs:

Purkinje cell protein 4 (PCP4), which modulates CaMKII activity, is downregulated in a CLN1 disease mouse model.
CaMKII expression increases in a CLN5 disease mouse model.
CaM-dependent protein kinase type 1D decreases in brain samples from CLN4 disease patients.
CaMKII and other CaMBPs are central to Alzheimer's disease progression, with recent work linking Alzheimer's to CLN5 mutations.

Using the CaM Target Database, researchers analyzed the 13 NCL proteins for putative CaM-binding domains (CaMBDs). The analysis revealed that 11 of the 13 NCL proteins contain putative CaMBDs, belonging to different motif subtypes. All 11 NCL proteins with putative CaMBDs have calcium-dependent binding motifs, suggesting that calcium signaling may primarily govern the regulation of NCL proteins by CaM.

The Future of NCL Therapies: Targeting Calmodulin?

The discovery that patient mutations overlap with putative CaMBDs in NCL proteins suggests that CaM may significantly contribute to NCL pathology. The two NCL proteins that lack putative CaMBDs, CLN7 and CLN11, are processed by CTSL, which contains a putative CaMBD, suggesting these NCL proteins are indirectly regulated by CaM through its interaction with CTSL.

Targeting CaM and its CaMBPs has shown promise in Huntington's disease treatment, where disrupting the binding of CaM to mutant huntingtin using a synthetic peptide led to neuroprotection. A similar approach targeting CaM in NCL models could yield similar results, suggesting CaM and/or CaM-regulated signaling may serve as a therapeutic target for NCLs.

Future research should focus on examining and validating CaM binding to NCL proteins, assessing the effects of NCL protein mutations on CaM binding, and exploring how CaM regulates NCL protein function. Understanding this relationship could explain how NCL proteins interact and pave the way for novel therapies to treat this devastating disease.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.3390/cells7110188, Alternate LINK

Title: Neuronal Ceroid Lipofuscinoses: Connecting Calcium Signalling Through Calmodulin

Subject: General Medicine

Journal: Cells

Publisher: MDPI AG

Authors: Sabateeshan Mathavarajah, Danton O’Day, Robert Huber

Published: 2018-10-29

Everything You Need To Know

What is Batten disease, and what are its main characteristics?

Batten disease, also known as Neuronal Ceroid Lipofuscinoses (NCLs), is a neurodegenerative disorder that affects individuals of all ages. It is characterized by vision loss, seizures, motor function decline, cognitive impairment, and a shortened lifespan. Currently, treatment options are limited, with Brineura being the only approved therapeutic, and it only targets a specific subtype (CLN2 disease). The condition arises from mutations in one of 13 identified genes (CLN1–8, CLN10–14), each encoding for different proteins involved in vital cellular processes. Because of the limited treatment options and the severity of symptoms this research is trying to provide a new avenue for understanding and treating the disease.

What is Calmodulin, and what does it do?

Calmodulin (CaM) is the primary calcium sensor within cells. It plays a crucial role in regulating a multitude of cellular processes. In response to calcium, CaM undergoes conformational changes, enabling it to bind to and regulate CaM-binding proteins (CaMBPs). These CaMBPs have diverse functions, including neuronal nitric oxide synthase, calcineurin A, calcium/CaM-dependent protein kinase II (CaMKII), and calcium channel proteins. CaM is central to regulating critical molecular pathways, including autophagy, apoptosis, adhesion, endocytosis, protein secretion, lipid metabolism, lysosomal dynamics, and DNA repair, all of which are also affected in various subtypes of NCLs.

Why is the connection between Calmodulin and Neuronal Ceroid Lipofuscinoses (NCLs) important?

The connection between Calmodulin (CaM) and Neuronal Ceroid Lipofuscinoses (NCLs) is significant because it highlights a potential new therapeutic target. Research indicates that 11 of the 13 NCL proteins contain putative CaM-binding domains (CaMBDs), suggesting that calcium signaling, mediated by CaM, may govern the regulation of NCL proteins. These findings suggest a novel therapeutic avenue and provides a deeper understanding of the disease pathology. These findings suggest that CaM plays a vital role in the cellular processes affected in NCLs. Targeting CaM could potentially help in managing the symptoms and slowing the progression of the disease.

How was the link between Calmodulin and NCL proteins discovered?

Scientists analyzed the 13 NCL proteins for potential Calmodulin (CaM)-binding domains (CaMBDs) using the CaM Target Database. The analysis revealed that 11 of the 13 NCL proteins contain putative CaMBDs. The identification of these binding domains supports the idea that CaM interacts directly with NCL proteins, affecting their function and, therefore, the progression of Batten disease. The two NCL proteins that lack the CaMBDs, CLN7 and CLN11, are processed by CTSL, which does contain a CaMBD, which suggests indirect regulation by CaM.

What are the implications of this research for the treatment of Batten disease?

The implications of this research suggest that targeting Calmodulin (CaM) could potentially lead to new therapies for Neuronal Ceroid Lipofuscinoses (NCLs). If CaM is a central player in regulating the processes affected in Batten disease, and many of the NCL proteins interact with CaM, then modulating CaM activity or its interactions with other proteins could provide an effective strategy to alleviate symptoms and slow disease progression. This understanding could potentially lead to the development of new treatments that address multiple subtypes of the disease, rather than just one as is currently the case with Brineura.